3,5-di-tertiary-butyl-4-hydroxyphenyl-1,3,4-thiadiazoles, and oxadiazoles and 3,5-di-tertiary-butyl-4-hydroxy-phenyl-1,2,4-thiadazoles, oxadiazoles and triazoles as antiinflammatory agents

ABSTRACT

The present invention is novel compounds which are 3,5-di-tertiary-butyl-4-hydroxyphenyl substituted 1,2,4- and 1,3,4-thiadazoles and oxadiazoles, and 1,2,4-triazoles, and pharmaceutically acceptable additions and base salts thereof, pharmaceutical compositions and methods of use therefor. The invention compounds are now found to have activity as inhibitors of 5-lipoxygenase and/or cyclooxygenase providing treatment of conditions advantageously affected by such inhibition including inflammation, arthritis, pain, fever, and the like.

This is a continuation of copending U.S. application Ser. No. 07/426,814filed Oct. 30, 1989, which is a continuation in-part of copending U.S.application Ser. No. 07/277,171 filed November 29, 1988, both nowabandoned.

BACKGROUND OF THE INVENTION

The present invention is novel compounds which are3,5-di-tertiary-butyl-4-hydroxyphenyl substituted 1,2,4- and1,3,4-thiadazoles and oxadiazoles, and 1,2,4-triazoles, andpharmaceutically acceptable acid addition or base salts thereof,pharmaceutical compositions and methods of use therefore. The inventioncompounds are now found to have activity as inhibitors of 5-lipoxygenaseand/or cyclooxygenase providing treatment of conditions advantageouslyaffected by such inhibition including inflammation, arthritis, pain,pyrrhia, and the like. Thus, the present invention is also apharmaceutical composition or method of use therefore.

U.S. Pat. No. 4,618,617 includes a generic disclosure for1,2,4-oxadiazole derivatives of groups which may be read to include3,5-di-tertiary butyl-4-hydroxy phenyl substituents. However, none ofthe disclosure specifically shows the unexpected activity of combinedring systems of the present oxadiazole and3,5-ditertiary-butyl-4-hydroxyphenyl groups. Similarly, J61005-072-A ofDerwent Abstract No. 86-051943/08 does not recognize the advantages ofthe present ring combination.

3,5-di-tertiary-butyl-4-hydroxyphenyl substituents are also shown onpyrrole ring-containing compounds in European Application No 269,981abstracted as Derwent Abstract No. 88-15622/423, showing usefulness asanalgesic, antipyretic, antiinflammatory, and antipsoriatic agents, andfor treating bone disorders.

A 3,5-di-tertiarybutyl-4-substituted benzylidene on a ##STR1## ring isdisclosed for use as antiinflammatory, analgesic, antipyretic, andantiplatelet aggregation agents in an abstract of Japanese Application88024498 in the Derwent Alerting Bulletin J8-B, Vol. 88, No. 21 byKanegafuchi Kagaku.

A 3,5-di-tertiarybutyl-4-hydroxybenzyl substituent for 2-pyrrolidonederivatives as antiinflammatory, analgesic, and antipyretic agents istaught by Japanese Application No. J63119-461 and J63115-859 in DerwentAbstract No. 88-180570/26 and 88-178973/26, respectively, by Eisai KK.

Other compounds disclosing either specifically or generically3,5-di-tertiarybutyl-4-hydroxy substituents include compounds that are,for example, 3-ethenylpyridines, in U.S. Pat. No. 4,743,606 abstractedin Derwent Abstract No. 88-147234/21 and ##STR2## wherein L is loweralkylene, sulphur or sulphinyl; and Y is alkoxyimino, or oxo; A--B-- isCH--CH₂ -- or C═CH--; and Z is lower alkylene or sulphur; in JapaneseApplication No. J62,081,343 in Derwent Abstract 87-140934/20.

Also, thiazolidinone derivatives are shown in European Application No.211670 by Eli Lilly and Co. of Derwent Abstract No. 87-051809/08 andthiazole derivatives in Japanese Application No. 62132871 by YamanouchiPharm KK discussed in Derwent Abstract No. 87-203585/29. In the Lillydisclosure the ring systems were linked by a saturated carbon group.

Thus, the differences between the present invention and the teachings ofthe references are readily apparent.

SUMMARY OF THE INVENTION

The present invention is a compound of the formula (I) ##STR3## and apharmaceutically acceptable acid addition or base salt thereof andhydrates; wherein n is zero or one, and W is ##STR4## wherein X is N,NR₁, O, or S wherein R₁ is hydrogen or lower alkyl;

Z is O, S, NR₁ or N wherein R₁ is independently as defined above; withthe proviso that when Z is NR₁ or N at the same time that X is N or NR₁then X must be N when Z is NR₁ and X must be NR₁ when Z is N and alsowith the proviso that when X is S or O then Z must be N, and that when Zis S or O then X must be N, i.e. one of either X or Z must be N;

Y is (1) C--SR₁ wherein R₁ is independently as defined above, (2)##STR5## wherein R₂ is lower alkyl (3) ##STR6## wherein R₂ is as definedabove, (4) C--NR₁ R₃ wherein R₁ is independently as defined above and R₃is hydrogen or lower alkyl, (5) COR₁ wherein R₁ is independently asdefined above, (6) CR₄ wherein R₄ is halogen, CF₃, CO₂ R₁, or ##STR7##CH₂ OR₁, Phenyl, ##STR8## NR₁ OR₃, S(CH₂)_(m) CO₂ H, CN, H, alkyl,NH(CH₂)_(m) OH, CCl₃, CONR₁ R₃, CSNR₁ R₃, CH₂ X₁₀, CH₂ NR₁₁ R₁₃,NHCSNHCO₂ R₂, CH₂ SR₂, CH₂ SO₂ R₂, or NHNH₂, (7) ##STR9## wherein m is1, 2, or 3; R₁₁ and R₁₃ are hydrogen, lower alkyl or taken together withN form a saturated ring having from 4 to 6 carbons; X₁₀ is halogen orNO₂ ; R₅ is H, lower alkyl or OR₁ and R₁, R₂, and R₃ are independentlyas defined above.

The present invention is also a pharmaceutical composition for thetreatment of conditions advantageously affected by the inhibition of5-lipoxygenase and/or cyclooxygenase which comprises an amount effectivefor the treatment of the condition of a compound of the formula I andthe pharmaceutically acceptable acid addition or base salt thereoftogether with a pharmaceutically acceptable carrier. The condition ismeant to include, for example, arthritis or other inflammatory diseases,allergic diseases, pain, fever, and psoriasis, but preferablyinflammatory diseases.

The present invention is also a method for treatment of the condition asnoted above in a mammal, including humans, suffering therefrom with acompound of the formula I or the pharmaceutically acceptable acidaddition or base salt thereof, in unit dosage form. The invention alsoprovides for use of any such compound of formula I or salt thereof inthe manufacture of medical therapeutic agent.

Pharmaceutical composition or use of the compound or salt of formula Iis meant to include treatment understood to be prophylactic pertinent tothe foregoing named condition.

The preferred compounds of the formula I in the present inventioninclude:

5-[3,5-Bis(1,1-dimethylethyl)-4-hydroxyphenyl]-1,3,4-thiadiazole-2(3H)-thione,

5-[3,5-Bis(1,1-dimethylethyl)-4-hydroxyphenyl]-1,3,4-oxadiazol-2(3H)-one,

5-[3,5-Bis(1,1-dimethylethyl)-4-hydroxyphenyl]-1,3,4-oxadiazole-2(3H)-thione,

5-[2-[3,5-Bis(1,1-dimethylethyl)-4-hydroxyphenyl]ethenyl]-1,3,4-oxadiazole-2(3H)-one,

2,4-Dihydro-5-[2-[4-hydroxy-3,5-bis(1,1-dimethylethyl)phenyl]ethenyl]-3H-1,2,4-triazole-3-thione,

5-[3,5-Bis(1,1-dimethylethyl)-4-hydroxyphenyl]-2,4-dihydro-3H-1,2,4-triazol-3-one,

5-[3,5-Bis(1,1-dimethylethyl)-4-hydroxyphenyl]-2,4-dihydro-4-methyl-3H-1,2,4-triazol-3-one,

5-[2-[3,5-Bis(1,1-dimethylethyl)-4-hydroxyphenyl]ethenyl]-2,4-dihydro-3H-1,2,4-triazol-3-one,

5-[3,5-Bis(1,1-dimethylethyl)-4-hydroxyphenyl]-2,4-dihydro-3H-1,2,4-triazole-3-thione,and

5-[2-[3,5-Bis(1,1-dimethylethyl)-4-hydroxyphenyl]ethenyl]-1,3,4-oxadiazole-2(3H)-thione.

4-(5-amino-1,3,4-thiadiazol-2-yl)-2,6-bis(1,1-dimethylethyl)phenol,

N-[5-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-1,3,4-thiadiazol-2-yl]guanidineand the monohydrochloride salt thereof, and

5-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-1,3,4-thiadiazol-2-yl]cyanamide,and the 2-hydroxy-N,N,N-trimethylethanaminum salt thereof.

Of these the most preferred are:

5-[3,5-Bis(1,1-dimethylethyl)-4-hydroxyphenyl]-1,3,4-thiadiazole-2(3H)-thione,

4-(5-Amino-1,3,4-thiadiazol-2-yl)-2,6-bis(1,1-dimethylethyl)phenol,

N-[5-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-1,3,4-thiadiazol-2-ylguanidineand the monohydrochloride salt thereof, and

5-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-1,3,4-thiadiazol-2-yl]cyanamide,and the 2-hydroxy-N,N,N-trimethylethanaminum salt thereof.

DETAILED DESCRIPTION OF THE INVENTION

In the compounds of formula (I) the term "lower alkyl" includes an alkylgroup of from one to six carbons such as methyl, ethyl, propyl, butyl,and the like and isomers thereof. Halogen is chloro, bromo or fluoro.

The compounds I of the invention may exist as tautomers which arereadily determined from art recognized tautomerism. Such tautomers are,for example, represented by formula I' and II" as follows: ##STR10##wherein A is O, NH or S ##STR11## wherein A is OH, NH₂ or SH or##STR12## wherein A is OH, NH₂ or SH ##STR13## wherein A is O, NH, or S.

Appropriate compounds of formula (I) are useful in the free base form,in the form of base salts where possible, and in the form of acidaddition salts. The three forms are within the scope of the invention.In practice, use of the salt form amounts to use of the base form.Pharmaceutically acceptable salts within the scope of the invention maybe those derived from mineral acids such as hydrochloric acid andsulfuric acid; and organic acids such as ethanesulfonic acid,benzenesulfonic acid, p-toluenesulfonic acid, and the like, giving thehydrochloride, sulfamate, ethanesulfonate, benzenesulfonate,p-toluenesulfonate and the like, respectively, or those derived frombases such as suitable organic and inorganic bases. Examples ofpharmaceutically acceptable base addition salts with compounds of thepresent invention include organic bases which are nontoxic and strongenough to form such salts. These organic bases form a class whose limitsare readily understood by those skilled in the art. Merely for purposesof illustration, the class may be said to include mono-, di-, andtrialkylamines such as methylamine, dimethyamine, and triethylamine;mono-, di-, or trihydroxyalkylamines such as mono-, di-, ortriethanolamine; amino acids such as arginine and lysine; guanidine;choline N-methylglucosamine; N-methylglucamine; L-glutamine;N-methylpiperazine; morpholine; ethylenediamine; N-benzylphenethylamine;tris(hydroxymethyl)aminomethane; and the like. (See for example,"Pharmaceutical Salts," J. Pharm. Sci., 66(1):1-19 (1977).) Salts ofinorganic bases include sodium, potassium, calcium or the like.

The acid addition salts of said basic compounds are prepared either bydissolving the free base or acid of compound I in aqueous or aqueousalcohol solution or other suitable solvents containing the appropriateacid or base and isolating the salt by evaporating the solution, or byreacting the free base of compound I with an acid as well as reactingcompound I having an acid group thereon with a base such that thereactions are in an organic solvent, in which case the salt separatesdirectly or can be obtained by concentration of the solution. Salts canalso be prepared by adding base to an aqueous alcohol solution ofanother salt.

The compounds of the invention may contain geometric isomers. Thus, theinvention includes the individual isomers and mixtures thereof. Theindividual isomers may be prepared or isolated by methods known in theart.

In determining when a lipoxygenase, cyclooxygenase, or duallipoxygenase/cyclooxygenase inhibitor is indicated, of course interalia, the particular condition in question and its severity, as well asthe age, sex, weight, and the like of the subject to be treated, must betaken into consideration and this determination is within the skill ofthe attendant physician.

For medical use, the amount required of a compound of formula I orpharmacologically acceptable salt thereof to achieve a therapeuticeffect will, of course, vary both with the particular compound, theroute of administration, the mammal under treatment, and the particulardisorder or disease concerned. A suitable dose of a compound of formula(I) or pharmacologically acceptable salt thereof for a mammal sufferingfrom, or likely to suffer from any condition as described hereinbeforeis 0.1 μg-500 mg of the compound per kilogram body weight. In the caseof systemic administration, the dose may be in the range of 0.5 to 500mg of the compound per kilogram body weight, the most preferred dosagebeing 0.5 to 50 mg/kg of mammal body weight administered two or threetimes daily. In the case of topical administration, e.g., to the skin oreye, a suitable dose may be in the range 0.1 ng-100 μg of the compoundper kilogram, typically about 0.1 μg/kg.

In the case of oral dosing for the treatment or prophylaxis of arthritisor inflammation in general, due to any course, a suitable dose of acompound of formula (I) or physiologically acceptable salt thereof, maybe as specified in the preceding paragraph, but most preferably is from1 mg to 10 mg of the compound per kilogram, the most preferred dosagebeing from 1 mg to 5 mg/kg of mammal body weight, for example from 1 to2 mg/kg.

It is understood that the ordinarily skilled physician or veterinarianwill readily determine and prescribe the effective amount of thecompound to prevent or arrest the progress of the condition for whichtreatment is administered. In so proceeding, the physician orveterinarian could employ relatively low doses at first, subsequentlyincreasing the dose until a maximum response is obtained.

While it is possible for an active ingredient to be administered alone,it is preferable to present it as a pharmaceutical formulationcomprising a compound of formula (I) or a pharmacologically acceptableacid addition or base salt thereof and a pharmacologically acceptablecarrier therefore. Such formulations constitute a further feature of thepresent invention.

The formulations, both for veterinary and for human medical use, of thepresent invention comprise an active ingredient in association with apharmaceutically acceptable carrier therefore and optionally othertherapeutic ingredient(s). The carrier(s) must be `acceptable` in thesense of being compatible with the other ingredients of the formulationsand not deleterious to the recipient thereof.

The formulations include those in a form suitable for oral, pulmonary,ophthalmic, rectal, parenteral (including subcutaneous, intramuscular,and intravenous), intraarticular, topical, nasal, or buccaladministration. Such formulations are understood to include long-actingformulations known in the art.

The formulations may conveniently be presented in unit dosage form andmay be prepared by any of the methods well-known in the art of pharmacy.All methods may include the step of bringing the active ingredient intoassociation with the carrier which constitutes one or more accessoryingredients. In general, the formulations are prepared by uniformly andintimately bringing the active ingredient into association with a liquidcarrier or a finely divided solid carrier or both, and then, ifnecessary, shaping the product into the desired formulation.

Formulations of the present invention suitable for oral administrationmay be in the form of discrete units such as capsules, cachets, tablets,or lozenges, each containing a predetermined amount of the activeingredient; in the form of a powder or granules; in the form of asolution or a suspension in an aqueous liquid or nonaqueous liquid; orin the form of an oil-in-water emulsion or a water-in-oil emulsion. Theactive ingredient may also be in the form of a bolus, electuary, orpaste.

The usefulness of the compounds of the present invention as inhibitorsof the 5-lipoxygenase enzyme, cyclooxygenase, or in treating relateddiseases or conditions may be demonstrated by their effectiveness invarious standard test procedures. A description of each procedurefollows.

ARBL/ARBC WHOLE CELL 5-LIPOXYGENASE AND CYCLOOXYGENASE ASSAYS Materials

The rat basophilic leukemia cell line (RBL-1) was obtained from theAmerican Type Culture Collection (Rockville, Md).

Radioimmunoassay (RIA) kits of LTB₄ and PGF₂.sbsb.α were obtained fromAmersham (Arlington Heights, Ill.) and Seragen (Boston, Mass.),respectively.

All tissue culture media were obtained from GIBCO (Grand Island, N.Y.).

Method

RBL-1 cells are grown in suspension culture in Eagle's minimum essentialmedium supplemented with 12% fetal bovine serum at 37° C. in anincubator supplied with air-5% carbon dioxide. Cells are harvested bycentrifugation. They are washed with cold phosphate buffered saline pH7.4 (PBS; NaCl, 7.1 g; Na₂ HPO₄, 1.15 g; KH₂ PO₄, 0.2 g; and KCl, 0.2g/l). Cells are finally suspended in PBS containing 1.0 mM calcium at adensity of 2×10⁶ cells/ml. Cells are incubated with and without testagent (in DMSO) (1% DMSO is without effect on arachidonic acidmetabolism) for ten minutes at room temperature. Calcium ionophoreA23187 (5 μM) is added and cells are incubated for seven minutes at 37°C. The reaction is stopped by chilling the tubes on ice for ten minutes.Cells are separated by centrifugation and the supernatant is stored at-20°. Aliquots (100 μl) are analyzed for LTB₄ and PGF₂.sbsb.α usingradioimmunoassay kits as provided by the supplier.

Table 1 contains biochemical data obtained from this whole cell assay asIC₅₀ s which are calculated as the amount of test compound causing 50%inhibition of LTB₄ or PGF₂.sbsb.α formation.

                  TABLE 1                                                         ______________________________________                                                      ARBL      ARBC                                                  Example       IC.sub.50.sup. b (μM)                                                                IC.sub.50.sup. c (μM)                              ______________________________________                                         4            5.7       0.86                                                   8            10        8                                                      7            1.4       2.5                                                   15            4.5       5.5                                                   17            1.6                                                             10            1.4       0.13                                                  ______________________________________                                         .sup.b IC.sub.50 for LTB.sub.4 inhibition.                                    .sup.c IC.sub.50 for PGF.sub.2.sbsb.α inhibition.                  

Carrageenan-Induced Rat Foot Paw Edema-2 (CFE-2) Assay: Protocol

Carrageenan solution (1% w/v) is prepared by dissolving 100 mgcarrageenan (Marine Colloidal Div., Springfield, N.J.) in 10 ml ofsterile saline (0.9%) solution (Travenol). The solution is vortexed for30 to 45 minutes. Animals are dosed with compound one hour beforecarrageenan challenge. Foot paw edema is induced by injecting 0.10 ml ofthe 1% carrageenan subcutaneously into the plantar portion of the righthind paw of each rat under light anesthesia. Initial foot paw volume ismeasured immediately following carrageenan challenge using mercuryplethysmography (Buxco Electronics). Edema is measured five hours aftercarrageenan. The difference between the five-hour and the initial pawvolume is expressed as delta edema. The delta edema for each test groupof animals is used to calculate the percent inhibition of edema achievedby the compound at the test dose compared with the vehicle controlgroup. The ID₄₀ (the dose at which swelling is inhibited by 40%) iscalculated by probit analysis for the dose at which 40 percentinhibition occurs.

Mycobacterium--Induced Rat Footpad Edema Assay (MFE): Protocol

Mycobacterium butyricum (5 mg/ml) is suspended in paraffin oil bysonication for ten minutes in an ice bath. Footpad edema is induced onDay 0 by injecting 0.1 ml of the Mycobacterium mixture into the lefthindpaw of lightly anesthetized rats. Swelling in the injected hindpawis determined by mercury plethysmography 72 hours after injection.Groups of rats are treated with test compounds (suspended in 0.5%hydroxypropyl methylcellulose with 0.2% Tween-80) or vehicle one hourbefore Mycobacterium injection and on Days 1 and 2. Inhibition ofswelling is determined by comparing the change in hindpaw volume incompound- and vehicle-treated rats. An ID₄₀ (the dose at which swellingis inhibited by 40%) is calculated by probit analysis.

Gastric Ulcerogenicity (UD): Protocol

Male outbred Wistar rats (100-250 gms) are fasted for 24 hours. Afterfasting, test compounds are administered orally (in 2 ml/kg of 0.5%hydroxypropyl methylcellulose) and the rats are denied access to foodand water for six more hours. The rats are then sacrificed with CO₂ sothat the stomachs can be removed, opened along the greater curvature,and evaluated for the presence of gastric ulcers. Results are expressedas the percent of rats with gastric ulcers at a given dose or as theUD₅₀ (the dose which causes ulcers in 50% of the rats).

The results of the CFE-2, MFE, and UD assays for each of the notedcompounds are shown in the following Table 2.

                  TABLE 2                                                         ______________________________________                                        In Vivo Pharmacology                                                          Compound  CFE-2.sup.a   MFE.sup.b                                                                             UD.sub.50.sup. c                              ______________________________________                                        Example 4.sup.d                                                                         1.9           3.2     N @ 200                                       ______________________________________                                         .sup.a ID.sub.40 in mg/kg, PO.                                                .sup.b ID.sub.40 in mg/kg, PO.                                                .sup.c Dose in mg/kg PO which produces a 50% occurrence of ulcers in rats     N is 0% of rats having ulcers at 200 mg.                                      .sup.d Compound tested as its sodium salt.                               

In addition to the compounds of formula I, the pharmaceuticalcompositions can also contain other active ingredients, such ascyclooxygenase inhibitors, nonsteroidal antiinflammatory drugs (NSAIDs),peripheral analgesic agents such as zomepirac, diflunisal, and the like.The weight ratio of the compound of the formula I to the second activeingredient may be varied and will depend upon the effective dose of eachingredient. Generally, an effective dose of each will be used. Thus, forexample, when a compound of the formula I is combined with an NSAID, theweight ratio of the compound of the formula I to the NSAID willgenerally range from about 1000:1 to about 1:1000, preferably about200:1 to about 1:200. Combinations of a compound of the formula I andother active ingredients will generally also be within theaforementioned range, but in each case, an effective dose of each activeingredient should be used.

Combinations of a compound of the formula I and other active ingredientswill generally be in the aforementioned ratios.

NSAIDs can be characterized into five groups:

(1) the propionic acid derivatives;

(2) the acetic acid derivatives;

(3) the fenamic acid derivatives;

(4) the biphenylcarboxylic acid derivatives; and

(5) the oxicams

or a pharmaceutically acceptable salt thereof.

The propionic acid derivatives which may be used comprise: ibuprofen,ibuprufen aluminum, indoprofen, ketoprofen, naproxen, benoxaprofen,flurbiprofen, fenoprofen, fenbufen, pirprofen, carprofen, oxaprozin,pranoprofen, miroprofen, tioxaprofen, suprofen, alminoprofen, tiaprofen,fluprofen, and bucloxic acid. Structurally related propionic acidderivatives having similar analgesic and antiinflammatory properties arealso intended to be included in this group.

Thus, "propionic acid derivatives' as defined herein are nonnarcoticanalgesics/nonsteroidal antiinflammatory drugs having a free--CH(CH₃)COOH or --CH₂ CH₂ COOH group (which optionally can be in theform of a pharmaceutically acceptable salt group, e.g., --CH(CH₃)COO⁻NA⁺ or --CH₂ CH₂ COO⁻ Na⁺), typically attached directly or via acarbonyl function to a ring system, preferably to an aromatic ringsystem.

The acetic acid derivatives which may be used comprise: indomethacin,which is a preferred NSAID, sulindac, tolmetim, zomepirac, diclofenac,fenclofenac, alclofenac, ibufenac, isoxepac, furofenac, tiopinac,zidometacin, acemetacin, fentiazac, clidanac, oxpinac, and fenclozicacid. Structurally related acetic acid derivatives having similaranalgesic and antiinflammatory properties are also intended to beencompassed by this group.

Thus, "acetic acid derivatives" as defined herein are nonnarcoticanalgesics/nonsteroidal antiinflammatory drugs having a free --CH₂ COOHgroup (which optionally can be in the form of a pharmaceuticallyacceptable salt group, e.g. --CH₂ COO⁻ Na⁺), typically attached directlyto a ring system, preferably to an aromatic or heteroaromatic ringsystem.

The fenamic acid derivatives which may be used comprise: mefanamic acid,meclofenamic acid, flufenamic acid, niflumic acid, and tolfenamic acid.Structurally related fenamic acid derivatives having similar analgesicand antiinflammatory properties are also intended to be encompassed bythis group.

Thus, "fenamic acid derivatives" as defined herein are nonnarcoticanalgesics/nonsteroidal antiinflammatory drugs which contain the basicstructure: ##STR14## which can bear a variety of substituents and inwhich the free --COOH group can be in the form of a pharmaceuticallyacceptable salt group, e.g., --COO⁻ Na⁺.

The biphenylcarboxylic acid derivatives which can be used comprise:diflunisal and flufenisal. Structurally related biphenylcarboxylic acidderivatives having similar analgesic and antiinflammatory properties arealso intended to be encompassed by this group.

Thus, "biphenylcarboxylic acid derivatives" as defined herein arenonnarcotic analgesics/nonsteroidal antiinflammatory drugs which containthe basic structure: ##STR15## which can bear a variety of substituentsand in which the free --COOH group can be in the form of apharmaceutically acceptable salt group, e.g., --COO--Na⁺.

The oxicams which can be used in the present invention comprise:piroxicam, sudoxicam, isoxicam, and 4-hydroxyl-1,2-benzothiazine1,1-dioxide 4-(N-phenyl)-carboxamide. Structurally related oxicamshaving similar analgesic and antiinflammatory properties are alsointended to be encompassed by this group.

Thus, "oxicams" as defined herein are nonnarcoticanalgesics/nonsteroidal antiinflammatory drugs which have the generalformula: ##STR16## wherein R is an aryl or heteroaryl ring system.

The following NSAIDs may also be used: acemetacin, alminoprofen, amfenacsodium, aminoprofen, anitrazafen, antrafenine, auranofin, bendazaclysinate, benzydamine, beprozin, broperamole, bufezolac, carprofen,cinmetacin, ciproquazone, clidanac, cloximate, dazidamine, deboxamet,delmetacin, detomidine, dexindoprofen, diacerein, di-fisalamine,difenpyramide, emorfazone, enfenamic acid, enolicam, epirizole,etersalate, etodolac, etofenamate, fanetizole mesylate, fenclofenac,fenclorac, fendosal, fenflumizole, fentiazac, feprazone, floctafenine,flunixin, flunoxaprofen, fluproquazone, fopirtoline, fosfosal,furcloprofen, furofenac, glucametacin, guaimesal, ibuproxam, isofezolac,isonixim, isoprofen, isoxepac, isoxicam, lefetamine HCl, leflunomide,lofemizole, lonazolac calcium, lotifazole, loxoprofen, lysin,clonixinate, meclofenamate sodium, meseclazone, microprofen, nabumetone,nictindole, nimesulide, orpanoxin, oxametacin, oxapadol, oxaprozin,perisoxal citrate, pimeprofen, pimetacin, piproxen, pirazolac,pirfenidone, pirprofen, pranoprofen, proglumetacin maleate, proquazone,pyridoxiprofen, sudoxicam, suprofen, talmetacin, talniflumate,tenoxicam, thiazolinobutazone, thielavin B, tiaprofenic acid, tiaramideHCl, tiflamizole, timegadine, tioxaprofen, tolfenamic acid, tolpadol,tryptamid, ufenamate, and zidometacin.

Finally, NSAIDs which may also be used include the salicylates,specifically aspirin, and the phenylbutazones, and pharmaceuticallyacceptable salts thereof.

Pharmaceutical compositions comprising the formula I compounds may alsocontain as the second active ingredient, antihistaminic agents such asbenadryl, dramamine, histadyl, phenergan, and the like. Alternatively,they may include prostaglandin antagonists such as those disclosed inEuropean Patent Application 11,067 or thromboxane antagonists such asthose disclosed in U.S. Pat. No. 4,237,160. They may also containhistidine decarboxylase inhibitors such as α-fluoromethylhistidine,described in U.S. Pat. No. 4,325,961. The compounds of the formula I mayalso be advantageously combined with an H₁ or H₂ -receptor antagonist,such as for instance cimetidine, ranitidine, terfenadine, famotidine,temelastine, acrivastine, loratadine, cetrizine, tazifylline,azelastine, aminothiadiazoles disclosed in EP 81102976.8 and likecompounds, such as those disclosed in U.S. Pat. Nos. 4,283,408;4,362,736; 4,394,508, and European Patent Application No. 40,696. Thepharmaceutical compositions may also contain a K⁺ /H⁺ ATPase inhibitorsuch as omeprazole, disclosed in U.S. Pat. No. 4,255,431, and the like.Each of the references referred to in this paragraph is herebyincorporated herein by reference.

The compounds of the formula I and their salts are prepared generally bythe following processes and constitute a further aspect of the presentinvention.

In the following processes ##STR17## where n is 0 or 1.

Under certain circumstances as discussed below, it is necessary toprotect the phenolic OH of Ar in various intermediates to give QAr whereQAr is ##STR18## where Q is a suitable oxygen protecting group,preferably methoxyethoxymethyl (MEM) and where n=0 or 1.

The MEM group is removed later using 1) Lewis acids such as ZnBr₂ inhalogenated solvents such as methylene chloride, chloroform, anddichloroethane at 0° to 60° C., 2) mineral acids such as HCl, HBr, orHNO₃ in solvents such as water, alkanols, tetrahydrofuran, diakylethers,dioxane, glyme, diglyme at 0° to 60° C. or 3) organic acids such asacetic acid in the solvents described in 1) and 2) at 0° to 60° C.

Introduction and removal of such suitable oxygen protecting groups arewell-known in the art of organic chemistry; see for example "ProtectiveGroups in Organic Chemistry," J. F. W. McOmie, ed., (New York, 1973),pages 43ff, 95ff, J .F .W. McOmie, Advances in Organic Chemistry, Vol.3, 159-190 (1963); J. F. W. McOmie, Chem. & Ind., 603 (1979), and T. W.Greene, "Protective Groups in Organic Synthesis", Wiley (New York) 1981,Chapters 2, 3, and 7.

Examples of suitable oxygen protecting groups are benzyl, trialkylsilyl,ethoxyethyl, methoxyethoxymethyl, methoxymethyl, trialkylsilylethyl, andthe like.

In the process described herein for the preparation of compounds of thisinvention the requirements for protective groups are generally wellrecognized by one skilled in the art of organic chemistry, andaccordingly the use of appropriate protecting groups is necessarilyimplied by the processes of the charts herein, although such groups maynot be expressly illustrated.

The method of preparation for compounds 7, 8, and 9 in Scheme 1 fromcompound 1, where n=0, are illustrated below. The phenolic OH of theknown nitrile 1 is protected to give 2 using Q halogen, preferablyMEMCl, in the presence of bases such as trialkylamines andalkalihydrides in ether solvents such as diethyl ether,diisopropylether, t-butylmethylether, tetrahydrofuran, dioxane, glyme ordiglyme; or chlorinated solvents such as dichloromethane, chloroform,dichloroethane, or carbon tetrachloride; or aromatic solvents such asbenzene, toluene, xylene, mesitylene or chlorinated benzenes at -10° to200° C. for up to five days. Compound 2 is treated with NaNHNH₂, LiNHNH₂or KNHNH₂ to give amidrazone 3 in ether solvents at 0° to 60° C. Thereaction of amidrazone 3 with 1,1-carbonyldimidazole, phosgene,diphosgene or triphosgene in the presence of trialkylamines in ethersolvents or chlorinated solvents at 0° to 200° C. for up to five daysgives triazolone 4. In a similar manner, compound 5 is prepared from 3using 1,1-thiocarbonyldiimidazole or thiophosgene as reagents. Compound6 is prepared from 3 using carbon disulfide in chlorinated or aromaticor ether solvents or alkanols at 0° to 200° C. for up to five days.Compounds 4, 5, and 6 are deprotected as described above to give 7, 8and 9. ##STR19##

The procedures which may be used for the preparation of compounds 2 to 4of Scheme 2 from compound 1 where n=0 or 1 are described below.

Compounds of structure 4 in Scheme 2 are prepared by treating oxime 1with N-chlorosuccinimide in dimethylformamide (DMF) or dimethylsulfoxide(DMSO), or chlorinated or aromatic or ether solvents at 0° to 60° C. forup to five days to give 2. Compound 3 is prepared by treating 2 withhydrazine and trialkylamine, if only one equivalent of hydrazine isused, in ether solvents or alkanols at 0° to 60° C. for up to five days.Treatment of 3 with CS₂ in DMF or DMSO or chlorinated or aromatic orether solvents or alkanols or neat at 0° to 60° C. for up to five daysgives 4.

Compounds of structure 4 and 5 in Scheme 3 where n=0 or 1 are preparedby the following procedures.

Compound 3 is prepared from 1 using 2 in DMF or DMSO or chlorinated orether solvents at 0° to 60° C. for up to five days. In addition, R₂ incompound 2 is defined as K⁺ or Na⁺ or Li⁺ to give 4 where R₂ istransformed to H after treatment with acid. Treatment of 3 with acid,such as aryl sulfonic acids or alkylsulfonic acids or mineral acids, inchlorinated or aromatic or ether solvents at 0° to 150° C. for up tofive days gives 4. Compound 5 is prepared from 4 using sodium or lithiumor potassium alkythiolates, or KCN, NaCN in DMF at 0° to 150° C. for upto five days. ##STR20##

The following procedures for preparing compounds 6 to 11 of Scheme 4from compound 1 of Scheme 4 where n=0 or 1 are described below.Conversion of 1 to 2 is effected using thionyl chloride or oxalylchloride and a catalytic amount of DMF in chlorinated or ether solventsat 0° to 100° C. for up to five days. Compound 4 is prepared from 2using 3 in chlorinated, aromatic or ether solvents at 0° to 120° C. forup to five days. Treatment of 4 with mineral acids in water and ethersolvents or alkanols gives hydrazide 5. Compound 6 is prepared from 5using alkylisothiocyanates in ether solvents or alkanols at 0° to 100°C. for up to five days followed by aqueous NaOH and refluxing thereaction mixture.

Compound 7 is prepared by reacting 5 with alkylisocyanate as describedfor the preparation of 6. Treatment of 5 with 1,1-carbonyldiimidazole orphosgene or diphosgene or triphosgene in chlorinated or ether solventsin the presence of trialkylamines at 0° to 100° C. for up to five daysgives 8. Treatment of 5 with CS₂ in the presence of one equivalent ofKOH in alkanols at 0° to 150° C. gives oxadiazolethione 9.

Treatment of 9 with hydrazine in water and alkanols at 0° to 150° C. forup to five days gives 11. Compound 10 is prepared from 5 using sodiumisocyanate, neutralized with one equivalent of a mineral acid, inalkanols at 0° to 100° C. for up to five days. ##STR21##

Compounds 4 and 5 of Scheme 5 are prepared from compound 1 as describedbelow. The acid chloride 1 is converted to 3 using thiosemicarbazide 2in ether solvents at 0° to 100° C. for up lo five days. Treatment of 3with alkyl or arylsulfonic acids in aromatic or ether solvents at 80° to150° C. for up to five days gives 4. Compound 5 is prepared from 3 usinga base such as sodium, lithium, or potassium alkoxides in alkanols at60° to 150° C. for up to five days. ##STR22##

The methods for the preparation of compounds 6-13 in Scheme 6 where X₁is O, S or NR₁ and R₆ is H, lower alkyl, phenyl, CH₂ Br, CH₂ Cl or CH₂NO₂, and R₇ is lower alkyl, phenyl, or CF₃, and R₈ is SO₂ R₂, CN or SO₂aryl, and R₉ is Cl, SR₂, SOR₂, SO₂ R₂, OR₂ or Oaryl are described below.The conversion of 1 where n=0 or 1 to 8, 10, and 13 is effected using 3,4, and 5, respectively, in solvents such as tetrahydrofuran,diethylether, diisopropyl ether, t-butylmethylether, dioxane, benzene,toluene, acetonitrile, DMF or DMSO at 0° to 150° C. for up to five days.Treatment of 1 with 1,1-carbonyldiimidazole, phosgene, diphosgene, ortriphosgene in the presence of trialkylamine in aromatic or ethersolvents gives 6. Compound 11 is prepared from 10 where X₁ is O, S orNR₂ and n=0 using lithium, sodium or potassium amide 14 in ethersolvents. The conversion of 8 to 9 and 11 to 12 is effected using P₂ S₅or Lawesson's reagent in ether solvents at 20° to 150° C. for up to fivedays.

Compound 7 is prepared from 1 using trialkylorthoesters 2 neat or inalkanols, aromatic or ether solvents in the presence of a catalyticamount of acid such as aryl or alkyl sulfonic acid or mineral acids.##STR23##

A method of preparing compound 3 from 1 in Scheme 7 where n=0 isdescribed below. The aminoguanidine HCl, H₂ SO₄ or HNO₃ salt isneutralized with a sodium, lithium or potassium alkoxide in an alkanolor ether solvent and then treated with 1. The reaction is run at 20° to150° C. for up to five days to give 2. Deprotection of 2 using the abovedescribed conditions gives 3. ##STR24##

The preparation of substituted 1,2,4-oxadiazoles is well known in theart (see, for example, L. B. Clapp, Advances in Heterocyclic Chem., 20,65 (1976)).

For a compound of Formula I, wherein n is zero and W is ##STR25##wherein X is O, Z is N, and Y is C--NH₂ the procedure of K. R. Huffmanand F. C. Schaefer, J. Org. Chem., 28, 1812 (1963), beginning with asuitable imino ester, may be used. Other functional groups, instead ofamino, are prepared by the procedures cited below.

    ______________________________________                                        ______________________________________                                        C--OH     F. Eloy, A. Deryckere and A. van                                              Overstraeten, Bull. Soc. Chim. Belges,                                        78, 47 (1969); and O. Tsuge, S. Urano, and                                    K. Oe, J. Org. Chem., 45, 5130 (1980).                              C--Halogen                                                                              F. Eloy, cited above; and G. R. Humphreys                                     and S. H. B. Wright, J. Heterocyclic                                          Chem., 26, 23 (1989).                                               C--SH     D. S. Tarbell and D. K. Fukushima, Organic                                    Syntheses, 27, 81 (1947).                                           C--SR.sub.2                                                                             B. W. Nash, R. A. Newberry, R. Pickles,                                       and W. K. Warburton, J. Chem. Soc.(c),                                        2794 (1969).                                                        C--R.sub.2                                                                              M. Yamamoto, U.S. Pat. No. 4,618,617 (1986).                        ______________________________________                                    

wherein R₂ is as defined above.

For a compound of Formula I, wherein n is zero and W is ##STR26##wherein X is N, Z is O, and Y is C--NH₂. The procedure of F. Eloy and R.Lenaers, Helv. Chim. Acta, 49, 1430 (1966), involving the reaction ofguanidine with a suitable carboxyimidoyl halide may be used. Otherfunctional groups, instead of amino, are prepared by the procedurescited below.

    ______________________________________                                        ______________________________________                                        C--OH      A. R. Katritzky, B. Wallis,                                                   R. T. C. Brownlee, and R. D. Topson,                                          Tetrahedron, 21, 1681 (1965).                                      C--Halogen T. Fujita, T. Fuji, and A. Ide,                                               Yakugaku Zasshi, 84, 1061 (1964).                                  C--SH,     M. Selim and M. Selim, Bull. Soc. Chim.                            C--SR.sub.2                                                                              Fr., 823 (1969); and R. M. Paton and                                          D. G. Hamilton, Tetrahedron Letters, 24,                                      5141 (1983).                                                       C--R.sub.2 S-Chiou and H. J. Shine, J. Heterocyclic                                      Chem., 26, 125 (1989).                                             ______________________________________                                    

Preparative procedures for substituted 1,2,4-thiadiazoles are also wellknown (see, for example, F. Kurzer, Advances in Heterocyclic Chem., 32,285 (1982)).

For a compound of Formula I, wherein n is zero and W is ##STR27##wherein X is N, Z is S, and Y is C-Halogen, the procedure of J.Goerdeler, H. Groschopp, and U. Sommerlad, Chem. Ber., 90, 182 (1957),consisting of condensing perchloromethylmercaptan with a suitableamidine, may be used. The resulting 5-halogen-substituted thiadiazole isthen treated with a variety of well-known reagents to prepare analogs inwhich Y is C--OH, C--SR₁, or C--NHR₁, wherein R₁ is as defined above.

A related synthetic procedure for compounds wherein Y is C--NH₂ is thatof J. Goerdeler, K. Wember, and G. Worsch, Chem. Ber., 87, 57 (1954).

For a compound of Formula I, wherein n is zero and W is ##STR28##wherein X is S, Z is N, and Y is C--NH₂ the procedure of C. G. Newton,W. D. Ollis, and D. E. Wright, J. Chem. Soc. Perk. Trans. I, 75 (1984),or B. Junge, German Patent 2,402,228 (1974), employing substitutedthioamides as starting materials, may be used.

When Y is C--OH, the procedure of O. Tsuge, et al, previously cited, orthat of J. Perronnet, L. Taliani, and A. Teche, U.S. Pat. No. 4,067,720(1978), may be advantageously employed.

Additional thiadiazole analogs are prepared by diazotization of aminesand other standard transformations.

Schemes 8-13 outline the functional group transformation which may beperformed on Y in compounds of formula I. ##STR29## wherein n, Y, X, andZ are described above.

Under certain circumstances discussed below the phenolic OH of 1 may beprotected as described above to give ##STR30## wherein Q is a protectinggroup as described above, and n, X, Y, and Z are described above.

Scheme 8 shows methods for the conversion of compounds of type 1 whereinY is C--OH (1) to compounds of type I wherein Y is C-OAlkyl (2) bytreatment of 1 with an alkyl halide in the presence of a base such asNaH, NaOH, KOH, KH, LiOH, t-BuOH or triethylamine.

Treatment of 1 with PCl₅, PCl₃, or POCl₃ in benzene, toluene, chloroformor methylene chloride gives a compound of type 3. Treatment of 4 understandard Sandmeyer reaction conditions also yields 3. ##STR31##

Scheme 9 shows processes for conversion of compounds of type 1 wherein Yis C--SH (1) to compounds 2, 3, 4, 5, 6, and 7.

Treatment of 1 with bases such as KH, NaH, or t-BuOK in the presence ofan omega-halocarboxylic lower alkylester in an aprotic solvent such asdiethylether, tetrahydrofuran or dimethyformamide, gives 2. Hydrolysisof 2 under standard basic conditions give the corresponding acid 4.

Treatment of 1 with alkyl halides under the conditions described abovegives 3.

Treatment of 3 with excess oxidizing agents such as KMnO₄, H₂ O₂ inacetic acid, or m-chloroperbenzoic acid (MCPBA) in choroform ormethylene chloride gives sulfone 5. Treatment of 3 with one equivalentof the above oxidizing agent gives sulfoxide 6.

Treatment of 1 with an oxidizing agent such as chlorine in acetic acidor sodium hyperchlorite, followed by an amine gives a sulfonamide oftype 7. ##STR32##

Scheme 10 shows the conversion of compounds of type I wherein Y isC--SO₂ R₂ (1), C--Cl (2) or C--CCl₃ (3) to compounds 4, 5, 6, 7, 8, 9,10, 11, 12, 13, and 14 on treatment with the nuceophiles listed inScheme 10.

Compounds 7, 12, 13, and 14 are prepared by treating 1, 2, or 3 with thesodium or potassium salt of the respective anion in a solvent such asDMF.

Compounds 4, 5, 6, 8, 9, 10, and 11 are prepared by treating 1, 2, or 3with the respective nucleophile in a solvent such as ethanol,isopropanol, tertiary butanol, or DMF/water. Triethylamine or sodiumtertiary butoxide are added in cases in which neutralization of an acidis required. ##STR33##

In Scheme 11 where R₅ is OR₂, R or aryl and R₁₀ is Cl, OR₂, SR₂,treatment of compounds of type I wherein Y is C--NH₂ with isocyanates orisothiocyanates in hexane, benzene or toluene gives compounds 2, 3, 4,and 5. Treatment of 1 with sodium nitrite in sulfuric acid, followed byhydrolysis of the diazonium salt gives 7. Alkylation, acylation, orsulfonylation of 1 with various electrophiles gives compounds 6, 8, 12,and 13. Amine 8 can be further treated with other electrophiles to yield9, 10, and 11. Amides 9 and 12 are converted to the correspondingthioamides 10 and 13 with treatment with P₂ S₅ or Lawesson's reagent.##STR34##

In Scheme 12, treatment of compounds of type I wherein Y is C--CH₂ Clwith various nucleophiles in dimethylsulfoxide or dimethylformamidegives 2, 3, and 4. Treatment of 4 with excess oxidizing agent such asKMnO₄, H₂ O₂ in acetic acid, or M-chloroperbenzoic acid (MCPBA) inchloroform or methylene chloride gives sulfone 5. ##STR35##

Methods for the preparation of 5, 6, and 7 in Scheme 13 are describedbelow. Compound 1 may be converted to 5, 6, or 7 using 2, 3, or 4,respectively, in aromatic, chlorinated or ether solvents at 0° to 200°C. The base such as sodium methoxide, potassium butoxide ortriethylamine may be needed to catalyze the reaction or to neutralizeacid that may be produced. This step is followed by treatment of thereaction with HNR₁ R₃ to give 5, 6, or 7, respectively.

Treatment of 8 in Scheme 13 with R₂ halogen in ether solvents in thepresence of a base such as sodium methoxide, potassium t-butoxide ortriethylamine at 0° to 150° C. gives 9. Compounds 5, 6 or 7 may beprepared from 9 using 10, 11, or 12, respectively, in aromatic or ethersolvents at 0° to 150° C. The anion of compound 10 may be generatedusing bases such as triethylamine, potassium t-butoxide, or sodiumhydride. The reactions using 11 and 12 could employ a base such aspotassium, sodium, t-butoxide, triethylamine. The phenolic OH of 1, 8,or 9 may be protected with Q as described above. ##STR36##

Compounds of formula I, where n=1, may also be prepared by Wittig-typereactions using the aldehyde 1 or 2 of Scheme 14 and phosphoranereagents of type 3 or with phosphonates of type 4 using a suitable basesuch as potassium or sodium alkoxide in a solvent such as DMSO or THF at-78° to 60° C. A base such as NaH or an alkyl lithium in a solvent suchas THF at -78° C. to reflux also may be used.

Alternatively, aldehydes of the type 5 of Scheme 14 (when suitablyprotected) may be reacted with phosphorane reagents of the type 6 orphosphonates of the type 7, under the conditions described above.

Reagents of the types 3, 4, 6, and 7 may be prepared by standard methodsfrom the corresponding halomethyl derivatives 8 or 9. ##STR37## whereinAr and QAr are as defined above and n=0

Hal=halogen

R₂ and W are defined above

An alternative is a Knoevenagel-type reaction using aldehyde 1 of Scheme15 with acid derivatives of type 2 or their esters (3) in a solvent suchas toluene or pyridine at reflux with a catalyst such as piperidine,piperidine/acetic acid, ammonium chloride, or ammonium acetate. For theesters 3, the intermediate 4 may be isolated, whereupon saponificationby standard methods, followed by a decarboxylation using, for example,copper quinoline at 100°-250° C. or diisopropylethylamine in a solventsuch as refluxing toluene, xylene, mesitylene, glyme, or diglyme wouldgive the compounds of formula I.

Reagents of type 2 and 3 may be prepared by standard methods, forexample, by reaction of the corresponding halomethyl heterocycle 5 withcyanide followed by hydrolysis of the nitrile. ##STR38## wherein Ar isas defined above and n=0

Hal=halogen

R₂ and W are as defined above

Using the Knoevenagel-type reaction, the aldehyde 1 of Scheme 16 and2-(5-thioxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)acetic acid (prepared bythe method described in Aust. J. Chem., 1979, 32, 161-5, N. W. Jacobsen,B. L. McCarthy, and S. Smith) in toluene/pyridine (2:1) is treated withpiperidine. The resulting mixture is refluxed to give thestyryltriazolethione.

Analogously, the aldehyde 1 of Scheme 16 is converted to thestyryltriazolone using2-(5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-yl)acetic acid (N. W. Jacobsen,B. L. McCarthy, and S. Smith, Aust. J. Chem., 1979, 32, 161-5).##STR39## Ar is as defined above wherein n=0.

Alternatively, treatment of the aldehyde 1 of Scheme 17 with a suitablyprotected methylheterocycle of Scheme 17 (using, for example, an alkyllithium reagent to form an anion of 2, followed by dehydration usingmethanolic HCl or toluenesulfonic acid in refluxing toluene) would givecompounds of the formula I. ##STR40##

One of skill in the art would recognize variations in the sequence andwould recognize variations in the appropriate reaction conditions fromthe analogous reactions shown or otherwise known which may beappropriately used in the processes above to make the compounds of theFormula I herein. Further, starting materials are known or can beprepared by known methods.

The products of the reactions described herein are isolated byconventional means such as extraction, distillation, chromatography, andthe like.

The invention is further elaborated by the representative examples asfollows. Such examples are not meant to be limiting.

EXAMPLE 13,5-Bis(1,1-dimethylethyl)-4-[(2-methoxyethoxy)methoxy]benzonitrile

2-Methoxyethoxymethyl chloride (4.1 g, 0.032 mole) is added dropwise toa 0° C. mixture of 3,5-bis(1,1-dimethylethyl)-4-hydroxybenzonitrile(Louis A. Cohen, Journal of Organic Chemistry 22, 1333, 1957) (5.0 g,0.022 mole) and diisopropylaminomethane (4.2 g, 0.032 mole) in methylenechloride (50 ml). The mixture is allowed to warm to room temperature andstir 18 hours. The solution is diluted with methylene chloride (25 ml)and washed with water (25 ml), cold 2M HCl (20 ml), saturated aqueousNaCl, and dried over MgSO₄. Filtered and concentrated in vacuo to obtain6.7 g (6.9 g theor., 97%) of3,5-bis(1,1-dimethylethyl)-4-[(2-methoxyethoxy)methoxy]benzonitrile as ayellow oil.

EXAMPLE 2 3,5-Bis(1,1-dimethylethyl)-4-(2-methoxyethoxy)methoxy]-benzenecarboximidic acid hydrazide

97% anhydrous hydrazine (4.8 g, 0.151 mole) is added dropwise to astirred 0° C. suspension of sodium hydride (2.8 g of a 60% dispersion inmineral oil, 0.071 mol) in tetrahydrofuran (70 m) under nitrogen. After90 minutes, a solution of3,5-bis(1,1-dimethylethyl)-4-[(2-methoxyethoxy)methoxy]benzonitrile (6.7g, 0.021 mole) in tetrahydrofuran (15 ml) is added dropwise. Afterstirring two hours at 0° C., water 2.4 ml) is added dropwise. Themixture is poured into cold, saturated aqueous sodium bicarbonate 20ml). The product is extracted with a 1:1 ethyl acetate/ether mixture (60ml). The organic layer is washed with saturated aqueous NaCl and driedover MgSO₄. Filtration and concentration provided a solid which wasrecrystallized from ethyl acetate/hexane to give 4.9 g (7.3 g theor.,67%) of 3,5-bis(1,1-dimethylethyl)-4-[(2-methoxyethoxy)methoxy]benzenecarboximidic acid hydrazide, mp 133° C.

EXAMPLE 35-[3,5-Bis(1,1-dimethylethyl)-4-[(2-methoxyethoxy)methoxy]phenyl]-1,3,4-thiadiazole-2(3H)-thione

Carbon disulfide (1.6 g, 0 021 mole) is added dropwise to a stirred 0°C. solution of3,5-bis(1,1-dimethylethyl)-4-[(2-methoxyethoxy)methoxy]benzenecarboximidic acid hydrazide (3.0 g, 0.085 mole) in absolute ethanol (36ml). The mixture is allowed to warm to room temperature and stir threehours. The mixture is stripped of volatiles under reduced pressure andthe residue is dissolved in isopropyl ether and the solvent removedunder reduced pressure. The resulting solid is recrystallized fromisopropyl ether/hexane to give 2.8 g of 5-[3,5-bis(1,1-dimethylethyl)-4-[(2-methoxyethoxy)methoxy]phenyl]-1,3,4-thiadiazole-2(3H)-thione (3.5g theor., 80%); mp 134°-135° C.

Calcd: C, 58.50; H, 7.36; N, 6.82.

Found: C, 58.65, H, 7.51, N, 6.81.

EXAMPLE 45-[3,5-Bis(1,1-dimethylethyl)-4-hydroxyphenyl]-1,3,4-thiadiazole-2(3H)-thione

Anhydrous zinc bromide (7.3 g, 0.033 mole) is added to a suspension of5-[3,5-bis(1,1-dimethylethyl)-4-[(2-methoxyethoxy)methoxyphenyl]-1,3,4-thiadiazole-2(3H)-thione(2.7 g, 0.007 mole) in methylene chloride (10 ml). After 18 hours themixture is diluted with methylene chloride (50 ml), washed with water(20 ml), saturated aqueous NaHCO₃ (20 ml), saturated aqueous NaCl (20ml), and dried over MgSO₄. Filtration and concentration gives a solidwhich is recrystallized from ethyl acetate/hexane to provide 1.1 g (2.1g theor., 52%) of5-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-1,3,4-thiadiazole-2(3H)-thione,mp 259.5°-260° C.

Calcd: C, 59.59; H, 6.88; N, 8.69.

Found: C, 59.65; H, 7.00; N, 8.65.

EXAMPLE 5 1,1-Dimethylethyl2-[3,5-bis(1,1-dimethylethyl)-4-hydroxybenzoyl]hydrazine carboxylic acid

Oxalyl chloride (11.4 g, 0.089 mole) is added dropwise to a stirred 0°C. solution of 3,5-bis(1,1-dimethylethyl)-4-hydroxybenzoic acid (15.0 g,0.059 mole) and 2 drops of dimethyl formamide in methylene chloride (200ml). After 30 minutes the solvent is removed in vacuo. The residue isdissolved in tetrahydrofuran (120 ml) and added dropwise to a stirred 0°C. suspension of 1,1-dimethylethyl hydrazine carboxylic acid intetrahydrofuran (200 ml). After 30 minutes, the solution is allowed towarm to room temperature and stir 18 hours. The mixture is concentratedin vacuo and the residue filtered through a plug of flash silica gelusing a petroleum ether eluent. Concentration and trituration with 1:2isopropyl ether/hexane yields 12.2 g (14.5 g theor., 84%) of1,1-dimethylethyl-2-[3,5-bis(1,1-dimethylethyl)-4-hydroxybenzoyl]hydrazinecarboxylic acid, mp 196.5° C.

Calcd C, 65.91; H, 8.85; N, 7.69.

Found: C, 66.05; H, 8.98; N, 7.60.

EXAMPLE 6 3,5-Bis(1,1-dimethylethyl)-4-hydroxybenzoic acid, hydrazide

1,1-Dimethylethyl2-[3,5-bis(1,1-dimethylethyl)-4-hydroxybenzoyl]hydrazine carboxylic acid(4.0 g , 0.011 mole) in tetrahydrofuran (100 ml) is treated with amixture of water (12 ml) and concentrated hydrochloric acid (30 ml). Theresulting mixture is heated on a steam-bath. After 20 minutes themixture is stripped of volatiles under reduced pressure. The residue isdissolved in water (100 ml) and treated with 1M NaOH until the solutionis slightly basic. The product is extracted into ether (600 ml) and theorganic layer is washed with saturated aqueous NaCl and dried overMgSO₄. Filtration and concentration provides a solid which isrecrystallized from isopropyl ether/hexane to yield 1.9 g (2.9 g theor.,66%) of 3,5-bis(1,1-dimethylethyl)-4-hydroxybenzoic acid, hydrazide, mp187°-188° C.

Calcd: C, 68.15; H, 9.15; N, 10.59.

Found: C, 68.33; H, 9.28; N, 10.35.

EXAMPLE 75-[3,5-Bis(1,1-dimethylethyl)-4-hydroxyphenyl]-1,3,4-oxadiazol-2(3H)-one

1,1'-Carbonyl diimidazole (0.8 g, 0.005 mole) is added in one portion toa stirred 0° C. solution of 3,5-bis(1,1-dimethylethyl)-4-hydroxybenzoicacid hydrazide (1.0 g, 0.004 mole) and triethylamine (0.6 ml, 0.004mole) in tetrahydrofuran (12 ml). After 18 hours the mixture isconcentrated in vacuo and the residue dissolved in ether. The solutionis washed with aqueous 2M HC, saturated aqueous NaHCO₃, saturatedaqueous NaCl, and dried over MgSO₄. Filtered and concentrated in vacuoto obtain a residue which is purified by flash chromatography using 10%ethyl acetate/hexane eluent. Recrystallize from ethyl acetate/hexane toobtain 0.6 g (1.1 g theor., 55%)5-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-1,3,4-oxadiazol-2(3H)-one,mp 246° C.

Calcd: C, 66.19; H, 7.64; N, 9.65.

Found: C, 66.24; H, 7.64; N, 9.63.

EXAMPLE 85-[3,5-Bis(1,1-dimethylethyl)-4-hydroxyphenyl]-1,3,4-oxadiazole-2(3H)-thion

Potassium hydroxide (1.1 g, 0.019 mole) is added in one portion to astirred 0° C. solution of 3,5-bis(1,1-dimethylethyl)-4-hydroxybenzoicacid hydrazide (5.0 g, 0.019 mole) and carbon disulfide (3.4 g, 0.044mole) in absolute ethanol (60 ml). The resulting mixture is stirred 30minutes at 0° C. before warming to room temperature and stirring onehour. The solution is then heated to reflux for 2.5 hours. The solventis removed in vacuo and the residue dissolved in water (100 ml) andwashed with ether. The aqueous layer is made acidic with 2M HCl and theproduct extracted with a 1:1 mixture of ethyl acetate/ether. The organiclayer is washed with saturated aqueous NaCl and dried over MgSO₄.Filtration and concentration gives a solid which is recrystallized fromethyl acetate/isopropyl ether to give 2.2 g (5.8 g theor., 38%) desired5-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-1,3,4-oxadiazole2(3H)-thione,mp 253.5° C.

Calcd: C, 62.72; H, 7.24; N, 9.14.

Found: C, 62.81; H, 7.29; N, 9.01.

EXAMPLE 92-[3,5-Bis(1,1-dimethylethyl)-4-hydroxybenzoyl]hydrazinecarbothioamide

Oxalyl chloride (11.5 g, 0.091 mole) is added dropwise to a stirred 0°C. solution of 3,5-bis(1,1-dimethyethyl)-4-hydroxybenzoic acid (15.0 g,0.059 mole) in methylene chloride (120 ml) and N,N-dimethylformamide(0.5 ml). After one hour, the solvent is removed in vacuo. The residueis dissolved in tetrahydrofuran (70 ml) and added dropwise to a stirred0° C. suspension of thiosemicarbazide (10.9 g, 0.120 mole) intetrahydrofuran (300 ml). After the addition is complete the mixture isallowed to warm to room temperature and stir 18 hours. The mixture isconcentrated in vacuo and the residue filtered through a plug of flashsilica gel using a 1:1 ethyl acetate/heptane mixture as eluent.Concentration and trituration with 1:1 isopropyl ether/hexane yielded17.6 g (19.4 g theor., 91%) of2-[3,5-bis(1,1-dimethylethyl)-4-hydroxybenzoyl]hydrazinecarbothioamide,mp 210°-211° C.

Calcd: C, 59.41; H, 7.79; N, 12.99.

Found: C, 59.47; H, 8.08; N, 13.21.

EXAMPLE 104-(5-Amino-1,3,4-thiadiazol-2-yl)-2,6-bis(1,1-dimethylethyl)phenol

Methanesulfonic acid (0.94 9, 0.010 mole) is added dropwise to a 0° C.suspension of2-[3,5-bis(1,1-dimethylethyl-4-hydroxybenzoyl]hydrazinecarbothioamide intoluene (19.5 ml). After the addition is complete the suspension isheated to reflux for four hours. The mixture is cooled to 10° C. andfiltered. The filtrate is washed with cold toluene. The solid issuspended in water (20 ml) and treated with concentrated NH<OH. Themixture is filtered, the solid washed with cold water (30 ml), and driedin vacuo to give 0.4 g of4-(5-amino-1,3,4-thiadiazol-2-y)-2,6-bis(1,1-dimethylethyl)-phenol (1.9g theor., 20%), mp 261° C.

Calcd (0.1 hydrate): C, 62.55; H, 7.61; N, 13.68.

Found: C, 62.32; H, 7.39; N, 13.40.

EXAMPLE 11 1,1-Dimethylethyl2-[3-[3,5-bis(1,1-dimethylethy)-4-hydroxyphenyl]-1-oxo-2-propenyl]hydrazinecarboxylicacid

Oxalyl chloride (2.9 g, 0.023 mole) is added dropwise to a stirred 0° C.solution of 3,5-bis(1,1-dimethylethyl)-4-hydroxycinnamic acid (4.3 g,0.016 mole) in methylene chloride (30 ml) and N,N-dimethylformamide (0.5ml . After one hour the solvent is removed in vacuo. The residue isdissolved in methylene chloride (30 ml) and added dropwise to a stirred0° C. solution of 1,1-dimethylethyl hydrazinecarboxylic acid (4.5 g,0.034 mole). After the addition is complete, the mixture is allowed towarm to room temperature and stir 18 hours. The mixture is concentratedin vacuo and the residue dissolved in methylene chloride (50 ml) andwashed with aqueous 2M HCl, saturated aqueous NaCl, and dried MgSO₄.Filtration and concentration gives a solid which was recrystallized fromethyl acetate/isopropyl ether to provide 4.6 g (6.1 g theor., 76%) of1,1-dimethylethyl2-[3-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-1-oxo-2-propenyl]hydrazinecarboxylicacid, mp 184° C.

EXAMPLE 12 3,5-Bis(1,1-dimethylethyl)-4-hydroxycinnamic acid hydrazide

1,1-Dimethylethyl2-[3-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-1-oxo-2-propenyl]hydrazinecarboxylicacid (4.3 g, 0.011 mole) in absolute ethanol (20 ml) is treated withaqueous 2M HCl (11.0 ml, 0.022 mole). The resulting mixture is heated ona steam-bath for one hour. The mixture is stripped of volatiles underreduced pressure and the residue partitioned between ether and water.The layers are separated and the aqueous phase is treated with saturatedaqueous NaHCO₃ until basic. The product is extracted out with a mixtureof 1:1 ethyl acetate/ether. The organic extract is washed with saturatedaqueous NaCl and dried over MgSO₄. Filtration and concentration providesa solid which is triturated in hot hexane and filtered to yield 3.0 g(3.2 g theor., 94%) of 3,5-bis(1,1-dimethylethyl)-4-hydroxycinnamic acidhydrazide, mp 166° C.

EXAMPLE 135-[2-[3,5-Bis(1,1-dimethylethyl)-4-hydroxyphenyl]ethenyl]-1,3,4-oxadiazole-2(3H)-one

Carbonyl diimidazole (0.7 g, 0.004 mole) is added in one portion to astirred 0° C. solution of 3,5-bis(1,1-dimethylethyl)-4-hydroxy-cinnamicacid hydrazide (1.0 g, 0.003 mole) and triethylamine (0.4 g, 0.004 mole)in tetrahydrofuran (12 ml). The mixture is stirred at 0° C. for 15minutes and then allowed to warm to room temperature and stir 45minutes. The solution is concentrated and the residue dissolved in ether(50 ml) and washed with aqueous 2M HCl. The product is extracted fromthe organic layer by treatment with aqueous 1M NaOH (20 ml). The aqueousextract is made acidic by treatment with cold aqueous 2M HCl and theproduct is extracted with ether. The organic layer is washed withsaturated aqueous NaCl and dried over MgSO₄. Filtration andconcentration provided a solid which was recrystallized from ethylacetate/hexane to give 1.0 g (1.1 g theor., 94%) of5-[2-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]ethenyl]-1,3,4-oxadiazole-2(3H)-one,mp >260° C.

Calcd: C, 68.33; H, 7.65; N, 8.85.

Found: C, 68.32; H, 7.71; N, 8.89.

EXAMPLE 14(E)-2,4-Dihydro-5-[2-[4-hydroxy-3,5-bis(1,1-dimethylethyl)phenyl]ethenyl]-3H-1,2,4-triazole-3-thione

A solution of 2-(5-thioxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)acetic acid(prepared by the method described in Aust. J. Chem., 1979, 32, 161-5,Nowel W. Jacobsen, Bruce L. McCarthy, Stephanie Smith) (3.3 g, 0.021mole) and 3,5-bis(1,1-dimethylethyl)-4-hydroxybenzadehyde (4.9 g, 0.021mole) in a 2:1 mixture of toluene/pyridine (300 ml) is treated withpiperidine (0.021 mole). The resulting mixture is stirred at reflux for48 hours. The mixture is concentrated in vacuo and the residue dissolvedin ether, the product is extracted from the organic phase with aqueous1M NaOH. The combined aqueous layers are made acidic by treatment withaqueous 2M HCl, and the product extracted with a 1:1 mixture of ethylacetate/ether. The organic layer is washed with saturated aqueous NaCland dried over MgSO₄. Filtration and concentration gives a solid whichis triturated in hot isopropyl ether and filtered to provide 2.3 g (6.9g theor., 33%) of desired(E)-2,4-dihydro-5-[2-[4-hydroxy-3,5-bis(1,1-dimethylethyl)phenyl]ethenyl]-3H-1,2,4-triazole-3-thione,mp 243° C.

Calcd: C, 65.22, H, 7.60; N, 12.68.

Found: C, 65.26; H, 7.83; N, 12.40.

EXAMPLE 155-[3,5-Bis(1,1-dimethylethyl)-4-hydroxyphenyl]-2,4-dihydro-3H-1,2,4-triazol-3-one

To a solution of 3,5-bis(1,1-dimethylethyl)-4-hydroxybenzoic acidhydrazine (2.8 g, 10.6 mmol) in ethanol (140 ml) and water (50 ml) isadded 1N HCl (16 ml) and sodium cyanate (1.03 g, 16 mmol). The reactionmixture is stirred at room temperature for 30 minutes and at 35° C. forfive minutes. The reaction mixture is cooled, evaporated, andpartitioned between water (100 ml) and ethyl acetate (100 ml). Theorganic layer is dried (MgSO₄) and evaporated. The crude product iscyclized by refluxing a solution in 1N NaOH (2-3 equiv.) for two hours.It is neutralized with 1N HCl and extracted with ethyl acetate. Pure5-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-2,4-dihydro-3H-1,2,4-triazol-3-one(0.32 g, 10%) is separated from 3,5-di-t-butyl-4-hydroxybenzoic acid byflash chromatography (silica, EtOAc), mp 276°-280° C.

Analysis: C₁₆ H₂₃ N₃ O₂.

Calcd: C, 66.41; H, 8.01; N, 14.52.

Found: C, 66.31; H, 8.10; N, 14.36.

EXAMPLE 165-[3,5-Bis(1,1-dimethylethyl)-4-hydroxyphenyl]-2,4-dihydro-4-methyl-3H-1,2,4-triazol-3-one

Methyl isocyanate (1.02 g, 18 mmol) is added dropwise to a solution ofthe 3,5-bis(1,1-dimethylethyl)-4-hydroxybenzoic acid, hydrazide (2.35 g,8.9 mmol) in absolute ethanol (100 ml). The reaction mixture is stirredat room temperature, concentrated, and poured into ice water. Theprecipitate (1.2 g) is collected by filtration and dissolved in twoequivalents of 1N NaOH. The reaction mixture is refluxed for threehours, and then is cooled and neutralized. The product is extracted intoethyl acetate. Pure5-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-2,4-dihydro-4-methyl-3H-1,2,4-triazol-3-one(0.8 g, 30%) is obtained by recrystallization from methanol, mp308°-312° C.

Analysis: C₁₇ H₂₅ N₃ O₂.

Calcd: C, 67.30; H, 8.31; N, 13.85.

Found: C, 67.04; H, 8.30; N, 13.67.

EXAMPLE 175-[2-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]ethenyl]-2,4-dihydro-3H-1,2,4-triazol-3-one

A solution of 3,5-di-t-butyl-4-hydroxybenzaldehyde (3.5 g, 15 mmol),2-(5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl) acetic acid (N. W. Jacobsen,B. L. McCarthy, and S. Smith, Aust. J. Chem., 32 161-5 (1979] (2.15 g,15 mmol), and piperidine (1.3 g, 15 mmol) in pyridine (15 ml) andtoluene (45 ml) is heated at reflux (with removal of water) for 40hours. The reaction mixture is cooled, filtered, and evaporated. Theresidue is partitioned between ethyl acetate (100 ml) and 1N HCl (400ml). The organic layer is washed two additional times with 1N HCl (400ml) and then is dried (MgSO₄) and evaporated. The residue crystallizedupon addition of hot dichloromethane. Recrystallization from isopropylether/ethyl acetate gives5-[2-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]ethenyl]-2,4-dihydro-3H-1,2,4-triazol-3-one(2.49 g, 40%), mp 280°-284° C.

Analysis C₁₈ H₂₅ N₃ O₂ :

Calcd: C, 68.54; H, 7.99; N, 13.32.

Found: C, 68.50; H, 8.04; N, 13.30.

EXAMPLE 185-3,5-Bis(1,1-dimethylethyl)-4-[(2-methoxyethoxy)methoxy]phenyl]-3H-1,2,4-triazole-3-thione

1,1'-Thiocarbonyldiimidazole (0.64 g, 0.0036 mole) is added portionwiseto a stirred 0° C. solution of3,5-bis(1,1-dimethylethyl)-4-[(2-methoxyethoxy)methoxy]benzenecarboximidic acid hydrazide 1.0 g, 0.0028 mole) and triethylamine (0.43ml, 0.003 mole) in tetrahydrofuran (5.0 ml). After the addition iscomplete the mixture is heated to reflux for 1.5 hours. The solution iscooled and concentrated in vacuo. The residue is dissolved in ether (20ml) and the solution washed with aqueous 2M HCl, saturated aqueousNaHCO₃, saturated aqueous NaCl, and dried over MgSO₄. Filtration andconcentration in vacuo gives 0.94 g (1.1 g theor., 86%) product afterrecrystallization from ethyl acetate/isopropyl ether, mp 187° C.

EXAMPLE 195-[3,5-Bis(1,1-dimethylethyl)-4-hydroxyphenyl]-3H-1,2,4-triazole-3-thione

Anhydrous zinc bromide (6.6 g, 0.0292 mole) is added to a suspension of5-[3,5-bis(1,1-dimethylethyl)-4-[(2-methoxyethoxy)methoxy]phenyl]-3H-1,2,4-triazole-3-thione(2.4 g, 0.0058 mole) in methylene chloride (6.0 m). After 18 hours themixture is diluted with methylene chloride (30 ml), washed with water(15 ml), saturated aqueous NaHCO₃ (15 ml), saturated aqueous NaCl (10ml), and dried over MgSO₄. Filtration and concentration gives a solidwhich is recrystallized from ethyl acetate/isopropyl ether to provide0.8 g (1.8 g theor., 44%) of product, mp >250° C.

EXAMPLE 20 5-[2-[3,5-Bis(1,1-dimethylethyl)-4-hydroxyphenyl]ethenyl]-1,3,4-oxadiazole-2(3H)-thione

Potassium hydroxide (0.5 g, 0.0096 mole) is added in one portion to astirred 0° C. solution of 3,5-bis(1,1-dimethylethyl)-4-hydroxycinnamicacid hydrazide (2.8 g, 0.0096 mole) and carbon disulfide (1.7 g, 0.022mole) in absolute ethanol (15.0 ml). The resulting mixture is stirred1.5 hours at 0° C. before heating to reflux for four hours. The solutionis cooled and the solvent is removed in vacuo. The residue is dissolvedin water (50 ml) and washed with ether (20 ml). The aqueous layer ismade acidic with aqueous 2M HCl and the product extracted with a 1:1mixture of ethyl acetate/ether. The combined organic extracts are washedwith saturated aqueous NaCl and

dried over MgSO₄. Filtration and concentration gives a solid which isrecrystallized from ethyl acetate/hexane to give 1.4 g (3.2 g theor.,44%) desired product, mp 209.5° C.

Calcd: C, 65.03; H, 7.28; N, 8.43.

Found: C, 65.37; H, 7.66; N, 8.24.

EXAMPLE 215-[3,5-Bis(1,1-dimethylethyl)-4-hydroxyphenyl]-1,3,4-thiadiazole-2(3H)-thione

Step 1.

To a solution of the 3,5-bis(1,1-dimethylethyl)-4-hydroxybenzaldehydeoxime (Louis A. Cohen, J. Org. Chem. 1957, 22, 1333) (0.5 g, 2.0 mmole)in DMF (5.0 ml) cooled to 0° C. is added N-chlorosuccinimide (0.35 g,2.6 mmole) in small portions over 5 minutes. After the addition iscomplete the mixture is allowed to stir at 0° C. overnight.

The mixture is diluted with water (5 ml) and extracted with ethylacetate (2×10 ml). The combined organic layers are diluted with hexane(10 ml) and washed with water (2×10 ml), brine (2×10 ml), and dried(MgSO₄). Concentration gives 0.3 g (55%) of desired chlorohydroxamate,mp 138° C.

Step 2.

A solution of the above chlorohydroxamate (0.3 g, 1.1 mmole) intetrahydrofuran (5 ml) is added dropwise to a 0° C. suspension ofanhydrous hydrazine (0.25 g, 7.7 mmole) in tetrahydrofuran (5 ml) slowlyover 40 minutes. After the addition is complete the mixture is allowedto stir two hours at 0° C. The solution is poured into ice coldsaturated NaHCO₃ (5 ml). The aqueous layer was extracted with 1:1EtOAc/Et₂ O (2×10 ml). The combined organic layers are washed with brine(10 ml), and dried (MgSO₄). Concentration in vacuo gives 0.15 g (49%) ofdesired hydrazino-hydroxamate after recrystallization (EtOAc/isopropylether), mp 172°-175.5° C. (dec.)

Step 3.

To a solution of the hydrazino-hydroxamate (1.2 g, 4.3 mmole) inabsolute ethanol (5 ml) cooled to 0° C. is added carbon disulfide (0.71g, 9.3 mmole) dropwise. The resulting solution is stirred three hours atroom temperature. The mixture is concentrated and the residue dissolvedin ether 20 m). The product is extracted with cold 2M NaOH 2×10 ml). Thecombined aqueous layers are acidified with cold 2M HCl. The product isextracted out with 1:1 EtOAc/Et₂ O (2×15 ml). The organic extracts arewashed with brine (10 ml), and dried (MgSO₄). Concentration andrecrystallization (EtOH/H₂ O) provides 0.8 g (58%) of the desiredproduct after drying in vacuo at 60° C., mp 259°-260° C.

EXAMPLE 225-[3,5-Bis(1,1-dimethylethyl)-4-hydroxyphenyl]-1,3,4-thiadiazole-2(3H)-thione,ion(1-), 2-hydroxy-N,N,N-trimethylethanamiom (1:1) salt

Choline bioarbonate (46.6% aqueous solution, 0.0763 mole) is added to awarm solution of5-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-1,3,4-thiadiazole-2(3H)-thione(25.0 g, 0.0775 mole) in methanol (100 ml). After the addition iscomplete the mixture is heated to reflux for 1 hour, before cooling andconcentrating in vacuo. The residue is crystallized from hott-butyl-methyl ether, filtered, and dried in vacuo to give 23.9 g (32.9g theor., 73%)5-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl-1,3,4-thiadiazole-2(3H)-thione,ion(1-), 2-hydroxy-N,N,N-trimethylethanamium (1:1) salt, mp 190°-191° C.

Calcd: C, 59.26; H, 8.29, N, 9.87.

Found: C, 59.27; H, 8.38; N, 9.81.

EXAMPLE 235-[3,5-Bis(1,1-dimethylethyl)-4-hydroxyphenyl]-1,3,4-thiadiazole-2(3H)-thione,monosodium salt, trihydrate

To a slurry of5-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-1,3,4-thiadiazole-2(3H)-thione(52 g, 0.161 mole) in methanol (500 ml) and water (500 ml) is addedaqueous 1N NaOH (161 ml, 0.161 mole) at room temperature. After theaddition is complete, the solution is allowed to stir at roomtemperature for 1/2 hour. The methanol is removed in vacuo and theresulting aqueous mixture lyophilized. The resulting solid hydrated in aclosed oven at 20° C. under nitrogen for 48 hours. This provides 63.9 g(64.2 g, theor., 99.5%) of5-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-1,3,4-thiadiazole-2(3H)-thione,monosodium salt, trihydrate.

Calcd: C, 48.22; H, 6.83; N, 7.03.

Found: C, 48.48; H, 6.87; N, 6.97.

EXAMPLE 24 5-3,5-Bis(1,1-dimethylethyl)-4-hydroxyphenyl]-1,3,4-thiadiazole-2(3H)-thione,monosodium salt, pentahydrate

To a 0° C. solution of5-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-1,3,4-thiadiazole-2(3H)-thione(5.16 g, 0.0159 mole) in methanol (50 ml), is added aqueous 1.00M NaOH(15.9 ml, 0.0159 mole) dropwise. After the addition is complete thesolution is stirred one hour at room temperature before concentrating invacuo. The residue is slurried in toluene and concentrated. The productis transferred from the flask to a crystallizing dish and dried in vacuoat 80° C. for 48 hours to provide 5.5 g (5.5 g theor., 100%) of5-[3,4-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-1,3,4-thiadiazole-2(3H)-thione,monosodium salt.

Calcd: C, 55.79; H, 6.14; N, 8.13.

Found: C, 55.44; H, 6.18; N, 7.96.

The material is spread out on a crystallizing dish and subjected to anatmosphere of moist air for 48 hours. This provides 6.2 g (6.9 g theor.,90%) of5-3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-1,3,4-thiadiazole-2(3H)-thione,monosodium salt, pentahydrate (material melted over large temperaturerange).

Calcd: C, 44.23; H, 7.19; N, 6.45.

Found: C, 44.18; H, 7.25; N, 6.37.

EXAMPLE 25 5-[3,5-Bis(1,1-dimethylethyl)-4-hydroxyphenyl]-2,4-dihydro-3H-1,2,4-triazole-3-thione

Sodium methoxide (2.2 g, 0.041 mole) is added to a solution of2-[3,5-bis(1,1-dimethylethyl)-hydroxybenzoyl]-hydrazinecarbothioamide(4.0 g, 0.0124 mole) in methanol (50 ml). The resulting mixture isstirred at reflux under an atmosphere of nitrogen for 24 hours. Thesolution is cooled and concentrated in vacuo. The residue is dissolvedin water (25 ml) and washed with ether (2×20 ml). The aqueous layer isacidified with cold aqueous 2M HCl (25 ml) and the product extracted outwith a 1:1 mixture of ethyl acetate/ether (2×30 ml). The combinedorganic extracts are washed with saturated aqueous NaCl and dried overMgSO₄. Filtration and concentration gives a residue which is purified byflash chromatography (SiO₂, 30% ethyl acetate/hexane eluent). The solidproduct is recrystallized from ethyl acetate/hexane to give 2.3 g of5-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-2,4-dihydro-3H-1,2,4-triazole-3-thione.(3.8 g theor., 61%): mp 271 ° C.

Calcd: C, 62.92; H, 7.59; N, 13.76.

Found: C, 62.80; H, 7.68; N, 13.65.

EXAMPLE 265-[3,5-Bis(1,1-dimethylethyl)-4-hydroxyphenyl]-1,3,4,-thiadiazol-2(3H)-one

To a 0° C. solution of 3,5-bis(1,1-dimethylethyl)-4-hydroxy-benzenecarbothioic acid, hydrazide (2.0 g, 0.0072 mole) in tetrahydrofuran (10ml) is added triethylamine (0.39 g, 0.0039 mole) followed by carbonyldiimidazole (0.8 g, 0.0048 mole). The resulting mixture is stirred at 0°C. for one hour. Dilute with ether and extract product with 1M NaOH(2×). The combined aqueous layers are combined and made acidic withaqueous 6M HCl. The product is extracted with 1:1 ether/ethyl acetate.The combined organic extracts are washed with saturated aqueous NaCl andconcentration in vacuo provides 1.4 g (2.2 g theor., 64%) of5-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-1,3,4-thiadiazol-2(3H)-oneafter recrystallization from ethyl acetate/hexane: mp 229° C.

Calcd: C, 62.72; H, 7.24; N, 9.14.

Found: C, 62.81; H, 7.23; N, 9.15.

EXAMPLE 27N-[5-[3,5-Bis(1,1-dimethylethyl)-4-hydroxyphenyl]-1,3,4-thiadiazole-2-yl]-urea

A suspension of4-(5-amino-1,3,4-thiadiazol-2-yl)-2,6-bis(1,1-dimethylethyl)-phenol (1.0g, 0.0032 mole) in ether (5 ml) is added to a 0° C. solution ofN-carbonylsulfamyl chloride (0.46 g, 0.0032 mole) in ether (5 ml). Theresulting mixture is stirred 15 minutes before water (10 ml) is added.The mixture is diluted with ether and washed with 2M HCl and saturatedaqueous NaCl. Extract with aqueous 1M NaOH (3×). The combined aqueouslayers are made acidic with aqueous 2M HCl. The resulting precipitate isfiltered and washed with water to provide 0.6 g (1.2 g theor., 53%) ofN-[5-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-1,3,4-thiadiazole-2-yl]-ureaafter drying in vacuo at 50° C; mp >270° C.

Calcd: C, 58.59; H, 6.94; N, 16.08.

Found: C, 58.25; H, 6.93; N, 15.75.

EXAMPLE 284-(5-Amino-1,3,4-oxadiazol-2-yl)-2,6-bis(1,1-dimethylethyl)phenol

Cyanogen bromide (0.9 g, 0.0083 mole) is added to a solution of3,5-bis(1,1-dimethylethyl)-4-hydroxybenzoic acid, hydrazide (2.2 g,0.0083 mole) and sodium bicarbonate (0.7 g, 0.0083 mole) in dioxane (10ml)/water (10 ml). The resulting mixture is stirred two hours at roomtemperature. The solution is concentrated to half volume in vacuo andthe residue diluted with water. The resulting solid is filtered andrecrystallized from ethyl acetate/hexane to give 1.5 g (2.4 g theor.,58%) of4-(5-amino-1,3,4-oxadiazol-2-yl)-2,6-bis(1,1-dimethylethyl)-phenol afterdrying in vacuo at room temperature, mp 244°-245° C.

Calcd: C, 66.41; H, 8.01; N, 14.52.

Found: C, 66.31; H, 7.99; N, 14.39.

EXAMPLE 29(E)-4-[2-(5-amino-1,3,4-oxadiazol-2-yl)ethenyl]-2,6-bis(1,1-dimethylethyl)phenol

Cyanogen bromide (0.7 g, 0.0067 mole) is added to a solution of3,5-bis(1,1-dimethylethyl)-4-hydroxycinnamic acid, hydrazide (1.9 g,0.0067 mole) and sodium bicarbonate (0.56 g, 0.0067 mole) in dioxane (10ml)/water (10 ml). The resulting mixture is stirred two hours at roomtemperature. The solution is concentrated to half volume in vacuo andthe residue diluted with water. The resulting solid is filtered andrecrystallized from ethyl acetate/hexane to provide 1.1 g (2.1 g theor.,52%) of(E)-4-[2-(5-amino-1,3,4-oxadiazole-2-yl)ethenyl]-2,6-bis(1,1-dimethylethyl)phenolafter drying in vacuo at room temperature, mp 221° C.

Calcd: C, 68.54; H, 7.99; N, 13.32.

Found: C, 68.92; H, 7.97; N, 13.28.

EXAMPLE 30 (E)-3,5-Bis(1,1-dimethylethyl)-4-hydroxyphenyl]-2-propenoicacid, 2-(methylthio)thioxomethyl]hydrazide

Oxalyl chloride (10.3 g, 0.0815 mole) is added dropwise to a stirred 0°C. solution of 3,5-bis(1,1-dimethylethyl)-4-hydroxycinnamic acid (15.0g, 0.0543 mole) in tetrahydrofuran (50 ml) and N,N-dimethyformamide (0.5ml). After one hour the solvent is removed in vacuo. The residue isdissolved in tetrahydrofuran (75 ml) and added dropwise to a stirred 0°C. solution of methyl hydrazinecarbodithioate (7.9 g, 0.0652 mole).After the addition is complete, the mixture is allowed to warm to roomtemperature and stir 18 hours. The mixture is concentrated in vacuo andthe residue dissolved in ether (100 ml), and washed with aqueous 0.5MHCl, saturated aqueous NaCl, and dried over MgSO₄. Filtration andconcentration in vacuo gives a residue which is purified by flashchromatography (SiO₂) using 20% ethyl acetate/hexane eluent.Recrystallize from ethyl acetate/hexane to obtain 8.2 g (20.7 g theor.,41%) of (E)-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-2 -propenoicacid, 2-[(methylthio)thioxomethyl]hydrazide, mp 200.5° C.

Calcd: C, 59.96; H, 7.42; N, 7.36.

Found: C, 59.94; H, 7.45; N, 7.09.

EXAMPLE 31(E)-2,6-Bis(1,1-dimethylethyl)-4-[2-[5-(methylthio)-1,3,4thiadiazol-2-yl]ethenyl]phenol

p-Toluenesulfonic acid (1.6 g, 0.0087 mole) is added to a solution of(E)-3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl-2-(methylthio)thioxomethyl]propenoicacid, hydrazide (3.3 g, 0.0087 mole) in toluene. After heating at refluxfor one hour, the solution is cooled and concentrated. The resultingsolid is recrystallized from ethyl acetate/t-butyl-methyl ether toprovide 2.1 g (3.2 g theor., 66%) of(E)-2,6-bis(1,1-dimethylethyl)-[2-[5-(methylthio)-1,3,4-thiadiazol-2-yl]ethenyl]phenol,mp 194° C.

Calcd: C, 62.95; H, 7.23; N; 7.73.

Found: C, 63.24; H, 7.42; N, 7.66.

EXAMPLE 32(E)-2,6-Bis(1,1-dimethylethyl)-4-[2-[5-(methylsulfonyl)-1,3,4-thiadiazol-2-yl]ethenyl]-phenol

Monoperoxyphthalio acid, magnesium salt hexahydrate (1.4 g of a 80% puresolid, 0.0056 mole) is added portionwise to a 0° C. solution of(E)-2,6-bis(1,1-dimethylethyl)-4-[2-[5-(methylthio)-1,3,4-thiadiazol-2-yl]ethenyl]-phenol(1.0 g, 0.0028 mole) in methanol (15 ml) and water (7 ml). After theaddition is complete the solution is allowed to warm to room temperatureand stir for two hours. The mixture is then warmed on a steam bath for45 minutes before cooling and concentrating in vacuo. The residue isdissolved in ether and washed with saturated aqueous NaHCO₃, saturatedaqueous NaCl, and dried over MgSO₄. Filtration and concentration invacuo gives a residue which is purified by flash chromatography (SiO₂)using a 15% ethyl acetate/hexane eluent, followed by recrystallizationfrom ethyl acetate/hexane to give 0.22 g (1.1 g theor., 22%)(E)-2,6-bis(1,1-dimethylethyl)-4-[2-[5-(methylsulfonyl)-1,3,4-thiadiazol2-yl]ethenyl]phenol,mp 235° C.

Calcd: C, 57.84; H, 6.64; N, 7.09.

Found: C, 57.88; H, 6.77; N, 7.00.

EXAMPLE 332,6-Bis(1,1-dimethylethyl)-4-[5-(methylthio)-1,3,4-thiadiazol-2-yl]phenol

5-[3,5-Bis(1,1-dimethylethyl)-4-hydroxyphenyl]-1,3,4-thiadiazole-2(3H)-thione(3.0 g, 0.0093 mole) in tetrahydrofuran (15 ml) is added dropwise to astirred 0° C. suspension of sodium hydride (0.37 g of a 60% dispersionin mineral oil, 0.0093 mole) in tetrahydrofuran (15 ml) under nitrogen.After 30 minutes, a solution of iodomethane (1.5 g, 0.0102 mole) intetrahydrofuran (5 ml) is added dropwise. After stirring one hour at 0°C., ether (20 ml) is added and the resulting mixture is washed withaqueous 2M HCl (10 ml), saturated aqueous NaCl, and dried over MgSO₄.Filtration and concentration in vacuo, followed by recrystallizationfrom ether/hexane gives 2.6 g of2,6-bis(1,1-dimethylethyl)-4-[5-(methylthio)-1,3,4-thiadiazol-2-yl]phenol(3.1 g, theor., 83%), mp 122°-122.5° C.

Calcd: C, 60.68: H, 7.19; N, 8.32.

Found: C, 60.73; H, 7.19; N, 8.18.

EXAMPLE 34[[5-[3,5-Bis(1,1-dimethylethyl)-4-hydroxyphenyl-1,3,4-thiadiazol-2-yl]thio]aceticacid

Aqueous 1M NaOH (12.4 ml, 0.0124 mole) is added to 0° C. solution of5-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-1,3,4-thiadiazole-2(3H)-thione(2.0 g, 0.0062 mole) in methanol (20 ml). This is followed by additionof 2-bromoacetic acid (0.95 g, 0.0068 mole) in one portion. Theresulting mixture is allowed to stir four hours with periodic warming.The solution is concentrated in vacuo and the residue is partitionedbetween ether and water. The layers are separated and the aqueous phaseis made acidic with aqueous 6M HCl. The aqueous layer is extracted with1:1 ethyl acetate/ether (2×). The combined organic layers are washedwith saturated aqueous NaCl, and dried over MgSO₄. Filtration andconcentration in vacuo provides a solid which is recrystallized fromethyl acetate/hexane to give 1.6 g (2.4 g theor., 68%) of[[5-[3,5-bis(1,1-dimethyl-ethyl)-4-hydroxyphenyl]-1,3,4-thiadiazole-2-yl[thio]aceticacid, mp 187.5° C.

Calcd: C, 56.82; H, 6.36; N, 7.36.

Found: C, 56.64; H, 6.23; N, 7.13.

EXAMPLE 352,6-Bis(1,1-dimethylethyl)-4-[5-(methylsulfinyl)-1,3,4-thiadiazol-2-yl]phenol

30% aqueous hydrogen peroxide (1.7 g, 0.015 mole) is added to a stirredsolution of2,6-bis(1,1-dimethylethyl)-4-[5-(methylthio)-1,3,4-thiadiazol-2-yl]-phenol(5.0 g, 0.015 mole) in glacial acetic acid (20 ml). The resultingmixture is heated to 90° C. for three hours. The mixture is cooled andconcentrated in vacuo. The residue is purified by flash chromatography(SiO₂, 25% ethyl acetate/hexane eluent) to provide a solid which isrecrystallized from ethyl acetate/hexane to give 1.4 g of2,6-bis(1,1-dimethylethyl)-4-[5-(methylsulfinyl)-1,3,4-thiadiazol-2-yl]phenol(5.3 g theor., 26%), mp 141.2° C.

Calcd: C, 57.92; H, 6.87; N, 7.95.

Found: C, 58.16; H, 6.97; N, 7.95.

EXAMPLE 362,6-Bis(1,1-dimethylethyl)-4-[5-(methylsulfonyl)-1,3,4-thiadiazol-2-yl]phenol

m-Chloroperbenzoic acid (3.5 g of a 80-85% pure solid, 0.016-0.017 mole)is added portionwise to a 0° C. solution of2,6-bis(1,1-dimethylethyl)-4-[5-(methylthio)-1,3,4-thiadiazole-2-yl]-phenol(2.0 g, 0.0059 mole) in dichloromethane (15 ml). After the addition iscomplete the solution is stirred four hours at 0° C. The mixture isdiluted with dichloromethane (20 ml) and the resulting solution iswashed with saturated aqueous NaHCO₃ (20 ml), saturated aqueous NaCl (10ml), and dried over MgSO₄. Filtration and concentration in vacuoprovides a solid which is recrystallized from ethyl acetate/hexane togive 1.6 g of2,6-bis(1,1-dimethylethyl)-4-[5-(methylsulfonyl)-1,3,4-thiadiazol-2-yl]-phenolafter drying in vacuo (2.2 g theor., 73%), mp 156.5° C.

Calcd: C, 55.41; H, 6.56; N, 7.60.

Found: C, 55.23; H, 6.53; N, 7.56.

EXAMPLE 372,6-Bis(1,1-dimethylethyl)-4-(5-hydrazino-1,3,4-thiadiazol-2-yl)phenol

To a solution of2,6-bis(1,1-dimethylethyl)-4-[5-(methylsulfonyl)-1,3,4-thiadiazole-2-yl]-phenol(4.1 g, 0.0111 mole) in isopropyl alcohol (30 ml) is added hydrazine(5.0 g, 0.10 mole). The resulting mixture is heated at reflux for fourhours. The mixture is cooled and concentrated in vacuo. The residue isdissolved in 1:1 ethyl acetate/ether and washed with saturated aqueousNaCl and dried over MgSO₄. Filtration and concentration in vacuoprovides a solid which is recrystallized from ethanol/water to give 2.6g of2,6-bis(1,1-dimethylethyl)-4-(5-hydrazino-1,3,4-thiadiazol-2-yl)phenolafter drying in vacuo (3.6 g theor., 73%), mp 109°-122° C.

Calcd: C, 59.97; H, 7.55; N, 17.48.

Found: C, 59.99; H, 7.69; N, 17.45.

EXAMPLE 382,6-Bis(1,1-dimethylethyl)-4-[5-(methylamino)-1,3,4-thiadiazol-2-yl]phenol

To a solution of2,6-bis(1,1-dimethylethyl)-4-[5-(methylsulfonyl)-1,3,4-thiadiazole-2-ylphenol(2.0 g, 0.0054 mole) in ethanol (10 ml) is added 25% ethanolicmethylamine solution (15 ml), followed by triethylamine (0.6 g, 0.006mole). The resulting mixture is heated to reflux for three hours. Anadditional amount of 25% ethanolic methylamine (15 ml) solution is addedand the mixture is stirred overnight at reflux. The solution is cooledand the volatiles removed under reduced pressure. The residue ispurified by flash chromatography (SiO₂) using 30% ethyl acetate/hexaneeluent. Recrystallize from ethyl acetate/hexane to obtain 0.8 g (1.7 gtheor., 48%) of2,6-bis(1,1-dimethylethyl)-4-[5-(methylamino)-1,3,4-thiadiazol-2-yl]phenol,mp 207.5°-208° C.

Calcd: C, 68.92; H, 7.89; N, 13.15.

Found: C, 63.67; H, 7.96; N, 13.00.

EXAMPLE 39N-5-3,5-Bis(1,1-dimethylethyl)-4-hydroxyphenyl]-1,3,4-thiadiazole-2-yl]guanidine,monohydrochloride

A mixture of sodium tert-butoxide (0.8 g, 0.0082 mole) in tert-butanol(10 ml) is treated with guanidine hydrochloride (0.9 g, 0.0092 mole).The resulting mixture is stirred 30 minutes at room temperature.2,6-Bis(1,1-dimethylethyl)-4-[5-(methylsulfonyl)-1,3,4-thiadiazole-2-yl]phenol (1.0 g, 0.0027 mole) is then added. Theresulting mixture is heated to reflux, stirred overnight, then cooledand concentrated in vacuo. The residue is precipitated frommethanol/water and the solid is filtered and washed with water. Thesolid is dissolved in ether and treated with saturated ethereal HCl. Theresulting precipitate is recrystallized from ethanol/ether to give 0.8 gofN-[5-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-1,3,5-thiadiazol-2-ylguanidine,monohydrochloride after drying in vacuo (1.0 g theor., 74%), mp 275.5°C.

Calcd: C, 53.18; H, 6.83; N, 18.24.

Found: C, 52.83; H, 6.84; N, 18.07.

EXAMPLE 40[5-[3,5-Bis(1,1-dimethylethyl)-4-hydroxyphenyl]-1,3,4-thiadiazol-2-yl]cyanamide

To a solution of2,6-bis(1,1-dimethylethyl)-4-[5-(methylsulfonyl)-1,3,4-thiadiazol-2-yl]phenol(5.0 g, 0.0136 mole) in a mixture of DMF (20 ml) and water (5 ml) isadded cyanamide (5.0 g, 0.119 mole) and triethylamine (1.4 g, 0.0136mole). The mixture is heated to 80° C. and stirred overnight. Anadditional portion of cyanamide (2.5 g, 0.059 mole) is added and themixture is stirred six hours at 80° C. The reaction is cooled andpartitioned between water and ether. The aqueous layer is acidified with6M HCl (40 ml). The resulting precipitate is filtered and recrystallizedfrom acetonitrile/water to provide 3.4 g of[5-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-1,3,4-thiadiazole-2-yl]cyanamide(4.5 g theor., 76%) after drying in vacuo at 70° C., mp >250° C.

Calcd: C, 61.79; H, 6.71; N, 16.96.

Found: C, 61.93; H, 6.82; N, 16.94.

EXAMPLE 412,6-Bis(1,1-dimethylethyl)-4-[5-[(2-hydroxyethyl)amino]-1,3,4-thiadiazol-2-yl]phenol

To a solution of2,6-bis(1,1-dimethylethy)-4-[5-(methylsulfonyl)-1,3,4-thiadiazole-2-yl]phenol(4.0 g, 0.0109 mole) in isopropyl alcohol (15 ml) is added ethanolamine(1.9 g, 0.0326 mole). The resulting mixture is heated to reflux for 18hours. The reaction is cooled and concentrated in vacuo. The resultingsolid is recrystallized from methanol/water to give 3.2 g (3.8 g theor.,83%) of2,6-bis(1,1-dimethylethyl)-4-[5-[(2-hydroxyethyl)amino]-1,3,4-thiadiazol-2-yl]phenolafter drying in vacuo at 65° C., mp 212°-213.5° C.

Calcd: C, 61.86; H, 7.79; N, 12.02.

Found: C, 61.74; H, 7.64; N, 11.62.

EXAMPLE 425-[3,5-Bis(1,1-dimethylethyl)-4-hydroxyphenyl]-2,4-dihydro-4-methyl-3H-1,2,4-triazole-3-thione

Methyl isothiocyanate (4.2 g, 57.1 mmol) is added dropwise to a solutionof the 3,5-bis(1,1-dimethylethyl)-4-hydroxybenzoic acid, hydrazide (7.6g, 28.6 mmol) in 300 ml of absolute ethanol. The reaction mixture isstirred at room temperature for 12 hours, concentrated, and poured ontoice water. The precipitate is collected by filtration and dissolved in60 ml of 1N NaOH. The reaction mixture is refluxed for three hours, andthen is cooled and acidified with 3N HCl. The aqueous mixture isextracted with ethyl acetate (3×). The combined extracts are washed withsaturated aqueous NaCl, dried over Na₂ SO₄, and concentrated in vacuo togive a white solid. Recrystallization from 2-methoxyethanol 100 ml)gives 6.34 g (9.1 g, theor., 70%) of the triazolethione as a whitesolid, mp >300° C.

Cacld: C, 63.91; H, 7.89; N, 13.15.

Found: C, 63.94; H, 7.80; N, 13.13.

EXAMPLE 432,6-Bis(1,1-dimethylethyl)-4-[5-(methylthio)-2H-1,2,4-triazol-3-yl]phenol

A solution of 6.00 g (19.64 mmol) of triazolethione (Example 19) and 9.1g (60.0 mmol) of iodomethane in 50 ml of absolute ethanol is stirred at50° to 60° C. for 0.5 hour, then cooled to room temperature. Thereaction is treated with 300 ml aqueous 0.7N NaOH, stirred for 30minutes, and filtered. Recrystallization of the resulting solid fromethanol-water gives 5.26 g (6.27 g theor., 84%) of the S-methylatedproduct as a fluffy, white solid, mp 271°-272° C.

Calcd: C, 63.91; H, 7.89; N, 13.15; S, 10.04.

Found: C, 63.61; H, 7.89; N, 12.96; S, 9.86.

EXAMPLE 442,6-Bis(1,1-dimethylethyl)-4-[5-(methylsulfinyl)-2H-1,2,4-triazol-3-yl]phenol

A 50° C. solution of 1.0 g (3.13 mmol) of the methylthiotriazole(Example 43) in 50 ml of 95% ethanol is treated dropwise with a solutionof 0.92 g (2.98 mmol) of 80% monoperoxyphthalic acid, magnesium salt(MMPP) in 4.5 ml of water over 20 minutes. The resulting reactionmixture is stirred at 40° to 50° C. for two hours and concentrated invacuo. The residue is dissolved in ethyl acetate, extracted withsaturated aqueous NaHCO₃ (three times), water and brine, dried over Na₂SO₄ and concentrated in vacuo. Flash chromatography (SiO₂, 5%methanol-chloroform, 26×6.5 cm) followed by recrystallization fromacetone-water gives 0.30 g (1.05 g theor., 29%) of the sulfoxide as awhite solid, mp 135°-145° C.

Calcd: C, 60.87; H, 7.51; N, 12.53.

Found: C, 60.51; H, 7.41; N, 12.28.

EXAMPLE 452,6-(Bis(1,1-dimethylethyl)-4-[3-methylsulfonyl)-1H-1,2,4-triazol-5-yl]phenol

A 50° C. slurry of 2.05 g (6.42 mmol) of the methylthiotriazole (Example43) in 20 ml of absolute ethanol is treated with 3.9 g (6.3 mmol, 1.96equiv.) of 80% monoperoxyphthalic acid, magnesium salt (MMPP) in 16 mlof H₂ O. The reaction is warmed at 50° C. for six hours and cooled loroom temperature. The reaction is poured onto cold, saturated aqueousNaHCO₃ and filtered, washing with the NaHCO₃ solution and water.Recrystallization from ethanol-water gives 1.41 g (2.26 g theor., 62%)of the sulfone as a white solid, mp 286°-287° C.

Calcd: C, 58.10; H, 7.17; N, 11.96.

Found: C, 57.95; H, 7.38; N, 11.99.

EXAMPLE 465-[3,5-Bis(1,1-dimethylethyl)-4-hydroxyphenyl]-1,3,4-thiadiazole-2-carbonitrile

A solution of 0.52 g (1.41 mmol) of methyl sulfone (Example 36) and 0.15g (3.06 mmol, 2.17 equiv.) of NaCN in 4 ml dimethylformamide is warmedat 65° C. for 25 hours. An additional portion of NaCN is added and thereaction is warmed at 75° C. for 16 hours and 85° C. for one hour. Thereaction is poured onto 3N aqueous HCl and extracted with ethyl acetate(three times). The combined extracts are washed with brine, dried overNa₂ SO₄, and concentrated in vacuo. Flash chromatography (SiO₂, 230-400mesh, 15×4.5 cm, 15% ethyl acetate-hexane) gives 0.20 g of the nitrile.Recrystallization from cyclohexane gives 0.14 g (0.44 g theor., 31%) ofthe pure nitrile, mp 140°-140.5° C.

Calcd: C, 64.73; H, 6.71; N, 13.32.

Found: C, 64.99; H, 6.54; N, 13.32.

EXAMPLE 47 2,6-Bis(1,1-dimethylethyl)-4-(1,3,4-thiadiazol-2-yl)phenol

A solution of 2.00 g (7.13 mmol) of 3,5-bis(1,1-dimethylethyl)-4-hydroxybenzenecarbothioic acid, hydrazide (preparationis described in Gompper, R., Kutter, E., Schmidt, RR., Liebigs Ann.Chem. 1965, 684, 1374), 1.57 g (10.61 mmol) of triethylorthoformate and0.07 g (0.37 mmol) of p-toluenesulfonic acid in 30 ml of absoluteethanol is warmed at reflux for six hours, poured onto 200 ml of icewater and filtered. Recrystallization from t-butylmethylether-hexanegives 1.56 g (2.07 g theor., 75%) of the thiadiazole; mp 150°-151° C.

Calcd: C, 66.17; H, 7.64; N, 9.65; S, 11.04.

Found: C, 66.39; H, 7.64; N, 9.53; S, 10.89.

EXAMPLE 482,6-Bis(1,1-dimethylethyl)-4-(5-methyl-1,3,4-thiadiazol-2-yl)phenol

A solution of 1.00 g (3.51 mmol) of3,5-bis(1,1-dimethylethyl)-4-hydroxybenzenecarbothioic acid, hydrazidein triethylorthoacetate (10 ml) containing a catalytic amount ofp-toluenesulfonic acid is warmed at 100° C. for 20 h, cooled, andconcentrated in vacuo. Chromatography (SiO₂, 70-230 mesh, 10×3.5 cm, 50%ethyl acetate-hexane) followed by recrystallization from cyclohexanegives 0.70 g (1.09 g theor., 64%) of the 5-methylthiadiazole as a beigesolid, mp 177°-178° C.

Calcd: C, 67.07; H, 7.95; N, 9.20.

Found: C, 67.33; H, 7.96; N, 8.87.

EXAMPLE 492,6-(Bis(1,1-dimethylethyl)-4-[5-(trifluoromethyl)-1,3,4-thiadiazol-2-yl]phenol

A solution of 2.0 g (7.1 mmol) of3,5-bis(1,1-dimethylethyl)-4-hydroxybenzenecarbothioic acid, hydrazidein 15 m of tetrahydrofuran is added dropwise to a 0° C. solution of 2.1g (18.4 mmol) of trifluoroacetic anhydride in 20 ml of tetrahydrofuranunder a nitrogen atmosphere. The reaction is stirred at 0° C. to roomtemperature over three hours, room temperature for 19 hours, and atreflux for one hour. The cooled reaction mixture is partitioned between100 ml t-butylmethylether and 150 ml of water. The aqueous layer isextracted with t-butylmethylether (2×50 ml). The combined organicextracts are washed with 5% aqueous NaHCO₃ (2×30 ml), 3N aqueous HCl(2×30 ml), and brine (50 ml), dried over Na₂ SO₄, and concentrated invacuo to give a foam. Chromatography (flash, SiO₂, 70-230 mesh, 25%ethyl acetate-hexane, 13×3.5 cm) followed by recrystallization fromisopropanol-water gives 1.03 g (2.54 g theor., 41%) of the titlecompound, mp 96°-97° C.

Calcd: C, 56.97; H, 5.91; N, 7.82.

Found; C, 57.29; H, 6.31; N, 7.74.

EXAMPLE 505-[3,5-Bis(1,1-dimethylethyl)-4-hydroxyphenyl]-1,3,4-thiadiazole-2-carboxylicacid, methyl ester

A 0° C. solution of 2.8 g (22.8 mmol, 1.10 equiv.) ofmethylchlorooxalate in 40 ml of tetrahydrofuran is treated with asolution of 5.8 g (20.7 mmol) of3,5-Bis(1,1-dimethylethyl)-4-hydroxybenzenecarbothioic acid, hydrazide(preparation is described in Gomper R., Kutter, D., Schmidt, RR.(Liebigs. Ann. Chem. 1965, 684, 1374) in 40 ml of tetrahydrofuran over10 minutes. The reaction is stirred at room temperature for 48 hours andconcentrated in vacuo. Recrystallization from ethyl acetate-cyclohexanethen from cyclohexane (two times) gives 2.98 g (7.21 g theor., 41%) ofthe carbomethoxythiadiazole as a yellow solid; mp 154°-155° C.

Calcd: C, 62.04; H, 6.94; N, 8.04; S, 9.20.

Found: C, 61.74; H, 6.91; N, 7.86; S, 8.81.

EXAMPLE 515-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-1,3,4-thiadiazole-2-carboxamide

A solution of 2.0 ml (3.20 mmol) of 1.6M n-butyllithium in hexane isadded dropwise to liquid ammonia (3-5 ml) at -78° C. over 10 minutesunder a nitrogen atmosphere. The resulting white slurry is treatedslowly with 10 ml of tetrahydrofuran and the resulting mixture oflithium amide at -78° C. is treated dropwise with a solution of 1.08 g(3.10 mmol) of5-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-1,3,4-thiadiazole-2-carboxylicacid, methyl ester in 3 ml of tetrahydrofuran. The reaction is allowedto warm slowly to room temperature and stirred for a total of 18 hours.The reaction is quenched with 100 ml of saturated aqueous NH₄ Cl andextracted with t-butylmethylether (3×). The combined organic extractsare washed with brine, dried over Na₂ SO₄, and concentrated in vacuo togive a yellow solid. Chromatography (flash, SiO₂, 70-230 mesh, 30% ethylacetate-hexane) followed by recrystallization from toluene gives 0.68 g(1.03 g theor., 66%) of the desired product as a pale yellow solid, mp200°-201° C.

Calcd: C, 61.23; H, 6.95; N, 12.60.

Found: C, 61.39; H, 6.93; N, 12.40.

EXAMPLE 525-[3,5-Bis(1,1-dimethylethyl)-4-hydroxyphenyl]-1,3,4-thiadiazole-2-carbothioamide

A mixture of 1.5 g (4.5 mmol) of5-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-1,3,4-thiadiazole-2-carboxamideand 1.0 g (2.2 mmol) of P₂ S₅ in 20 ml of dioxane is warmed at refluxfor one hour under a nitrogen atmosphere. The reaction is poured througha plug of SiO₂, washing with t-butylmethylether. Recrystallization fromtoluene gives 0.45 g (1.6 g theor., 28%) of the thioamide as a yellowsolid, mp 215°-216° C.

Calcd: C, 58.42; H, 6.63; N, 12.02.

Found: C, 58.76; H, 6.80; N, 11.73.

EXAMPLE 533,5-Bis(1,1-dimethylethyl)-4-[(2-methoxyethoxy)methoxy]benzoic acid,methyl ester

2-Methoxyethoxy-methyl chloride (24.0 g, 192.7 mmol) is added dropwiseto a 0° C. mixture of 25.0 g (94.6 mmol) of3,5-bis(1,1-dimethylethyl)-4-hydroxybenzoic acid, methyl ester and 27.5g (212.4 mmol) of diisopropylethylamine in 50 ml of CH₂ Cl₂ under anitrogen atmosphere. The reaction is stirred at 25° C. for 24 hours andthen poured onto saturated aqueous NH₄ Cl and the layers are separated.The aqueous layer is extracted with t-butylmethyl ether (2×150 ml). Thecombined organic extracts are washed with saturated aqueous NH₄ Cl,water and brine (2×), dried over Na₂ SO₄, and concentrated in vacuo togive 33.2 g of the desired product as an orange oil. The product is pureenough to use in subsequent reactions. A sample can be purified bychromatography (flash, SiO₂, 230-400 mesh, 29×6.5 cm, 15%t-butylmethylether-hexane) followed by Kugelrohr distillation.

Calcd: C, 68.15; H, 9.15.

Found: C, 67.78; H, 9.09.

EXAMPLE 545-[3,5-Bis(1,1-dimethylethyl)-4-[(2-methoxethoxy)methoxy]phenyl]-1H-1,2,4-triazole-3-amine

A 0° C. slurry of 7.00 g (63.32 mmol) of aminoguanidine hydrochoride in30 ml of methanol is treated with 3.42 g (63.31 mmol) of sodiummethoxide. The mixture is treated dropwise with 5.60 g (15.89 mmol) of3,5-bis(1,1-dimethylethyl)-4-[(2methoxyethoxy)methoxy]benzoic acid,methyl ester in 20 ml of methanol over 30 minutes under a nitrogenatmosphere. The reaction is warmed at reflux for 40 hours and pouredonto 400 ml of ice water. The aqueous mixture is neutralized to pH 7using 3N HCl. The precipitate is collected and recrystallized fromtoluene to give 2.79 g (5.98 g theor., 47%) of the product as a whitesolid, mp 233°-235° C.

EXAMPLE 55 4-(3-Amino-1H-1,2,4-triazol-5-yl)-2,6-bis(1,1-dimethylethyl)phenol

Hydrogen chloride (g) is bubbled for 45 minutes through a slurry of 2.50g (6.66 mmol) of5-[3,5-bis(1,1-dimethylethyl)-4-[(2-methoxyethoxy)methoxy]phenyl]-1H-1,2,4-triazole-3-aminein 45 ml of methanol immersed in an ice bath. The reaction is exothermicand becomes homogeneous. The reaction is stirred for two hours at roomtemperature and concentrated in vacuo to give a foam. The residue isarmed in 50 ml of t-butylmethylether and allowed to cool to give a whitesolid. The solid is dissolved in aqueous 1N NaOH and extracted witht-butylmethylether (2×) and the aqueous layer is neutralized to pH 7with aqueous 3N HCl. The resulting solid is isolated by filtration andrecrystallized from acetonitrile-water to give 0.30 g (1.92 g, theor.,16%) of the aminotriazole as a white solid, mp >250° C.

Calcd: C, 66.64; H, 8.39; N, 19.43.

Found: C, 66.41; H, 8.32; N, 19.17.

EXAMPLE 563,5-Bis(1,1-dimethylethyl)-4-[(2-methoxyethoxy)methoxy]oximebenzamide

A mixture of 19.0 g (0.06 mole) of 3,5-bis(1,1-dimethylethyl)-4-[(2-methoxyethoxy)methoxy]benzonitrile and 3.0 g (0.09 mole) ofhydroxylamine in absolute ethanol (600 ml) is stirred and heated at80°-90° C. for 18 hours. The mixture is cooled and ethanol is evaporatedleaving a solid residue. Recrystallization from ethyl acetate and hexaneaffords 27.4 g (62%) of analytically pure3,5-bis(1,1-dimethylethyl)-4-[(2-methoxyethoxy)methoxy]oximebenzamide,mp 134°-135° C.

Analyzed for C₁₉ H₃₂ N₂ O₄ :

Calcd: C, 64.74; H, 9.15; N, 7.95.

Found: C, 64.73; H, 9.09; N, 7.83.

EXAMPLE 573,5-Bis(1,1-dimethylethyl)-N-[(ethoxycarbonyl)oxy]-4-[(2-methoxyethoxy]methoxy]benzenecarboximidamide

A solution of 2.5 g (0.007 mole) of 3,5-bis(1,1-dimethylethyl)-4-(2-methoxyethoxy)methoxy]oximebenzamide and 1.0 g(0.009 mole) of triethylamine in chloroform (15 ml) is treated with 0.8g (0.007 mole) of ethyl chloroformate over 10 minutes. The solution isstirred at room temperature for one hour, then washed with water (2×20ml). The organic layer is dried (anhydrous magnesium sulfate) andevaporated to yield a white solid. Recrystallization from chloroform andpetroleum ether affords 2.6 g (85%) of analytically pure3,5-bis(1,1-dimethylethyl)N-[(ethoxycarbonyl)oxy]-4-[(2-methoxyethoxy)methoxy]benzenecarboximidamide,mp 115°-117° C.

Analyzed for C₂₂ H₃₆ N₂ O₆ :

Calcd: C, 62.24; H, 8.55; N, 6.60.

Found: C, 62.50; H, 8.72; N, 6.66.

EXAMPLE 583-[3,5-Bis(1,1-dimethylethyl)-4-(2-methoxyethoxy)methoxy]phenyl]-1,2,4-oxadiazol-5(4H)-one

A solution of 5.0 g (0.012 mole) of3,5-bis(1,1-dimethylethyl)-N-[(ethoxycarbonyl)oxy]-4-[(2methoxyethoxy)methoxy]benzenecarboximidamidein toluene (150 ml) is stirred at 120°-130° C. for 18 hours. The tolueneis evaporated (vacuum) and the residual oil solidifies upon standing.The solid is recrystallized from ethyl acetate and hexane giving 3.1 g(70%) of analytically pure 3-[3,5-bis(1,1-dimethylethyl)-4-[(2-methoxyethoxy)methoxy]phenyl]-1,2,4-oxadiazol-5(4H)-one, mp112°-114° C.

Analyzed for C₂₀ H₃₀ N₂ O₅ :

Calcd: C, 63.46; H, 7.99; N, 7.40.

Found: C, 63.82; H, 8.05; N, 7.33.

EXAMPLE 593-[3,5-Bis(1,1-dimethylethyl)-4-hydroxyphenyl-1,2,4-oxadiazol-5(4H)-one

A mixture of 1.9 g (0.005 mole) of3-[3,5-bis(1,1-dimethylethyl)-4-[(2-methoxyethoxy)methoxy]phenyl]-1,2,4-oxadiazol-5(4H)-oneand 5.7 g (0.025 mole) of zinc bromide in dichloromethane (10 ml) isstirred vigorously at room temperature for three hours. Thedichloromethane is then carefully decanted and the white solid is washedwith additional dichloromethane (2×50 ml). The combined organic layersare washed with 10% sodium bicarbonate (2×50 ml), saturated sodiumchloride (2×50 ml) and dried (anhydrous magnesium sulfate).Concentration leaves a solid which is recrystallized from ethyl acetateand hexane giving 0.7 g (48%) of3-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-1,2,4-oxadiazol-5(4H)-one,mp 189°-191° C.

Analyzed for C₁₆ H₂₂ N₂ O₃ :

Calcd: C, 66.18; H, 7.64; N, 9.65.

Found: C, 65.84; H, 7.58; N, 9.34.

EXAMPLE 603,5-Bis(1,1-dimethylethyl)-4-[(2-methoxyethoxy)methoxy]-O-acetyloximebenzamide

In a manner analogous to Example 57, 6.0 g (0.017 mole) of3,5-bis(1,1-dimethylethyl)-4-(2-methoxyethoxy)methoxy]oximebenzamide isreacted with 1.3 g (0.017 mole) of acetyl chloride to give 4.5 g (68%)of analytically pure3,5-bis(1,1-dimethylethyl)-4-[(2-methoxyethoxy)methoxy]-O-acetyloximebenzamide,mp 134°-137° C.

Analyzed for C₂₁ H₃₄ N₂ O₅ :

Calcd: C, 63.93; H, 8.69; N, 7.10.

Found: C, 63.99; H, 8.87; N, 6.91.

EXAMPLE 613-[3,5-Bis(1,1-dimethylethyl)-4-[(2-methoxyethoxy)methoxy]phenyl]-5-methyl-1,2,4-oxadiazole

A solution of 4.0 g (0.01 mole) of3,5-bis(1,1-dimethylethyl)-4-[(2-methoxyethoxy)methoxy]-O-acetyloximebenzamidein xylene (125 ml) is stirred at 120°-130° C. for 18 hours. The xyleneis evaporated (vacuum) and the residual oil solidifies upon standing.The solid is recrystallized from ethyl acetate and hexane giving 3.0 g(81%) of analytically pure3-[3,5-bis(1,1-dimethylethyl)-4-[(2-methoxyethoxy)methoxy]phenyl]-5-methyl-1,2,4-oxadiazolemp 75°-77° C.

Analyzed for C₂₁ H₃₂ N₂ O₄ :

Calcd: C, 66.99; H, 8.57; N, 7.44.

Found: C, 67.21; H, 8.39; N, 7.37.

EXAMPLE 622,6-Bis(1,1-dimethylethyl)-4-(5-methyl-1,2,4-oxadiazol-3-yl)phenol

In a manner analogous to Example 59, 2.6 g (0.007 mole) of3-[3,5-bis(1,1-dimethylethyl)-4-[(2-methoxyethoxy)methoxy]phenyl]-5-methyl-1,2,4-oxadiazoleis reacted with 7.7 g (0.03 mole) of zinc bromide to give 0.94 g (48%)of 2,6-bis(1,1-dimethylethyl)-4 -(5-methyl-1,2,4-oxadiazo-3-yl)-phenol;mp 126°-127° C.

Analyzed for C₁₇ H₂₄ N₂ O₂ :

Calcd: C, 70.79; H, 8.39; N, 9.72.

Found: C, 70.78; H, 8.22; N, 9.61.

EXAMPLE 634-(5-Amino-1,2,4-oxadiazol-3-yl)-2,6-bis(1,1-dimethylethyl)phenol

To a solution of 2.6 g (0.044 mole) of guanidine in absolute ethanol(100 ml) is added dropwise a solution of 6.2 g (0.022 mole) of3,5-bis(1,1-dimethylethyl) -N,4-dihydroxybenzenecarboximidoyl chloridein absolute ethanol (60 ml). The mixture is stirred at room temperaturefor 18 hours, then evaporated to dryness (vacuum). The oil is dissolvedin ethyl acetate (125 ml) and poured into water (125 ml). Whilestirring, the solution is acidified (pH 4.0-5.0) with 1N hydrochloricacid. The organic layer is separated, washed with water (2×100 ml), anddried (anhydrous magnesium sulfate). Evaporation of the organic layerleaves 5.0 g of crude material. Purification by flash chromatography(silica gel, ethyl acetate/hexane elution) gives 1.0 g (16%) ofanalytically pure4-(5-amino-1,2,4-oxadiazol-3-yl)-2,6-bis(1,1-dimethylethyl)phenol, mp202°-204° C.

Analyzed for C₁₆ H₂₃ N₃ O₂ :

Calcd: C, 66.41; H, 8.01; N, 14.52.

Found: C, 66.56; H, 8.20; N, 14.56.

EXAMPLE 645-[3,5-Bis(1,1-dimethylethyl)-4-[(2-methoxyethoxy)methoxy]phenyl)-3-bromo-1,2,4-oxadiazole

To a vigorously stirred suspension of 9.5 g (0.030 mole) of3,5-bis(1,1-dimethylethyl)-4-[(2-methoxethoxy)methoxy]benzonitrile and3.9 g (0.050 mole) of sodium bicarbonate in toluene (5.0 ml) heated at90° C., is added 3.0 g (0.015 mole) of solid dibromoformaldoxime (G. R.Humphrey and S. H. B. Wright, J Heterocyclic Chem 26:23 (1989)) in smallportions over 20 minutes. After 18 hours at 90° C. the mixture iscooled, diluted with ethyl acetate (40 ml), washed with saturated sodiumchloride (2×40 ml), and dried (anhydrous magnesium sulfate). Evaporationof ethyl acetate leaves a brown oil. Purification by flashchromatography (silica gel, ethyl acetate/hexane elution) yields 1.6 g(25%) of analytically pure5-[3,5-bis(1,1-dimethylethyl)-4-[(2-methoxyethoxy)methoxyphenyl]-3-bromo-1,2,4-oxadiazole,mp 89°-91° C.

Analyzed for C₂₀ H₂₉ BrN₂ O₄ :

Calcd: C, 54.42; H, 6.62; N, 6.35.

Found: C, 54.73; H, 6.48; N, 6.31.

EXAMPLE 654-(3-Bromo-1,2,4-oxadiazol-5-yl)-2,6-bis(1,1-dimethylethyl)phenol

In a manner analogous to Example 59, 0.8 g (0.002 mole) of5-[3,5-bis(1,1-dimethylethyl)-4-[(2methoxyethoxy)methoxy]phenyl]-3-bromo-1,2,4-oxadiazoleis reacted with 2.0 g (0.009 mole) of zinc bromide to give 0.4 g (65%)of 4-(3-bromo-1,2,4-oxadiazol-5-yl)-2,6-bis(1,1-dimethylethyl)phenol, mp113°-115° C.

Analyzed for C₁₆ H₂₁ BrN₂ O₂ :

Calcd: C, 54.39; H, 5.99; N, 7.93.

Found: C, 54.53; H, 6.06; N, 7.88.

EXAMPLE 66 O-[3,5-Bis(1,1-dimethylethyl)-4-hydroxybenzoyl]oximeacetamide

A mixture of 1.7 g (0.007 mole) of 3,5-di-tert-butyl-4-hydroxybenzoicacid, 0.5 g (0.007 mole) of acetamidoxime (K. P. Fora, B. van't Riet,and G. L. Wampler, Cancer Research 38:1291 (1978)) and 0.9 g (0.007mole) of 1-hydroxy-benzotriazole hydrate (1-HBT) in DMF (35 ml) iscooled in an ice bath. N,N'-dicyclohexylcarbodiimide (1.5 g, 0.007 mole)is added and the mixture is stirred at room temperature for 18 hours.The reaction mixture is poured into ice water (60 ml) and extracted withethyl acetate (2×30 ml). The layers are separated, and the aqueous phaseis made basic with 10% sodium bicarbonate, then extracted with ethylacetate (50 ml). The organic layers are combined, filtered, and washedsuccessively with 10% sodium bicarbonate (2×50 ml) and water (2×50 ml),then dried over anhydrous magnesium sulfate. Evaporation of solventleaves a yellow solid. Purification by flash chromatography (silica gel,ethyl acetate/hexane elution) yields 1.3 g (62%) ofO-[3,5-bis(1,1-dimethylethyl) -4-hydroxybenzoyl]oximeacetamide, mp175°-176° C.

Analyzed for C₁₇ H_(26N) ₂ O₃ :

Calcd: C, 66.63; H, 8.55; N, 9.14.

Found: C, 66.59; H, 8.55; N, 9.04.

EXAMPLE 672,6-Bis(1,1-dimethylethyl)-4-(3-methyl-1,2,4-oxadiazol-5-yl)phenol

A solution of 4.2 g (0.01 mole) ofO-[3,5-bis(1,1-dimethylethyl)-4-hydroxybenzoyl]oximeacetamide in xylene(125 ml) is stirred at 120°-130° C. for 18 hours. The xylene isevaporated (vacuum) and the residual oil solidifies upon standing. Thesolid is recrystallized from ethyl acetate and hexane giving 2.4 g (62%)of analytically pure2,6-bis(1,1-dimethylethyl)-4-(3-methyl-1,2,4-oxadiazol-5-yl)phenol), mp126°-127° C.

Analyzed for C₁₇ H₂₄ N₂ O₂ :

Calcd: C, 70.79; H, 8.39; N, 9.72.

Found: C, 70.87; H, 8.34; N, 9.60.

EXAMPLE 682-Chloro-O-[3,5-bis(1,1-dimethylethyl)-4-hydroxybenzoyl]oximeacetamide

In a manner analogous to Example 66, 13.2 g (0.05 mole) of3,5-di-tert-butyl-4-hydroxybenzoic acid is reacted with 5.7 g (0.05mole) of 2-chloroacetamidoxime (Karl P. Flora, Bart van't Riet, andGalen L. Wampler, Cancer Research 38:1291 (1978)) in the presence of1-HBT (7.1 g, 0.05 mole) and N,N'-dicyclohexylcarbodiimide (12.0 g, 0.06mole). Evaporation of solvent leaves a solid. Purification by flashchromatography (silica gel, ethyl acetate/hexane elution) yields 12.1 g(67%) of2-chloro-O-[3,5-bis(1,1-dimethylethyl)-4-hydroxybenzoyl]oximeacetamide,mp 173°-175° C.

Analyzed for C₁₇ H₂₅ ClN₂ O₃ :

Calcd: C, 59.90; H, 7.39; N, 8.22.

Found: C, 60.00; H, 7.46; N, 8.18.

EXAMPLE 694-[3-(Chloromethyl)-1,2,4-oxadiazol-5-yl]-2,6-bis(1,1-dimethylethyl)phenol

A solution of 3.7 g (0.011 mole) of2-chloro-O-[3,5-bis(1,1-dimethylethyl)-4-hydroxybenzoyl]oximeacetamidein toluene (100 ml) is stirred at 120°-130° C. for 18 hours. The tolueneis evaporated (vacuum) and the residual oil solidifies upon standing.The solid is recrystallized from ethyl acetate and hexane giving 2.8 g(80%) of analytically pure4-[3-(chloromethyl)-1,2,4-oxadiazol-5-yl)-2,6-bis(1,1-dimethylethyl)phenol, mp 93°-94° C.

Analyzed for C₁₇ H₂₃ ClN₂ O₂ :

Calcd: C, 63.25; H, 7.18; N, 8.68.

Found: C, 63.25; H, 7.20; N, 8.66.

EXAMPLE 702,6-Bis(1,1-dimethylethyl)-4-[3-(1-pyrrolidinylmethyl)-1,2,4-oxadiazol-5-yl]phenol

A mixture of 0.5 g (0.002 mole) of 4-[3-(chloromethyl)-1,2,4-oxadiazol-5-yl]-2,6-bis(1,1-dimethylethyl)phenol and 0.4 g (0.006mole) of pyrrolidine in DMF (10 ml) is stirred at room temperature forthree hours. The mixture is poured into ice water (50 ml) and extractedwith ethyl acetate (3×25 ml). The organic phase is washed with water(3×40 ml), dried (anhydrous magnesium sulfate), and evaporated, leavingan oil. Purification by flash chromatography (silica gel, ethylacetate/hexane elution) yields 0.4 g (73%) of analytically pure2,6-bis(1,1-dimethylethyl)-4-[3-(1-pyrrolidinylmethyl)-1,2,4-oxadiazol5-yl]phenol, mp 100°-102° C.

Analyzed for C₂₁ H₃₁ N₃ O₂ :

Calcd: C, 70.55; H, 8.74; N, 11.76.

Found: C, 70.71; H, 8.82; N, 11.68.

EXAMPLE 714-[3-[(Dimethyamino)methyl]-1,2,4-oxadiazol-5-yl]-2,6-bis(1,1-dimethylethyl)phenol

In a manner analogous to Example 70, 0.5 g (0.002 mole) of4-[3-(chloromethyl)-1,2,4-oxadiazol-5-yl]-2,6-bis(1,1-dimethylethyl)phenolis reacted with excess dimethylamine gas to give 0.3 g (59%) ofanalytically pure4-[3-[(dimethyamino)methyl]-1,2,4-oxadiazol-5-yl]-2,6-bis(1,1-dimethylethyl)phenol,mp 129°-130° C.

Analyzed for C₁₉ H₂₉ N₃ O₂ :

Calcd: C, 68.85; H, 8.82; N, 12.68.

Found: C, 68.71; H, 9.01; N, 12.51.

EXAMPLE 722,6-Bis(1,1-dimethylethyl)-4-[3-[(methylamino)methyl]-1,2,4-oxadiazol-5-yl]phenol

In a manner analogous to Example 70, 0.8 g (0.002 mole) of4-[3-(chloromethyl)-1,2,4-oxadiazol-5-y]-2,6-bis(1,1-dimethylethyl)phenolis reacted with excess monomethylamine gas to give 0.2 g (31%) ofanalytically pure2,6-bis(1,1-dimethylethyl)-4-[3-[(methylamino)methyl]-1,2,4-oxadiazol-5-yl]phenol,mp 120°-122° C.

Analyzed for C₁₉ H₂₇ N₃ O₂ :

Calcd: C, 68.11; H, 8.57; N, 13.24.

Found: C, 68.11; H, 8.88; N, 13.12.

EXAMPLE 732,6-Bis(1,1-dimethylethyl)-4-[3-[(methylthio)methyl]-1,2,4-oxadiazol-5-yl]phenol

A mixture of 2.3 g (0.007 mole) of 4-[3-(chloromethyl)-1,2,4-oxadiazol-5-yl-2,6-bis(1,1-dimethylethyl)phenol and 0.7 g (0.009mole) of sodium thiomethoxide in methanol (90 ml) is heated at 75° C.for 1.5 hours. The solution is concentrated to one-third the volume (˜30ml) and diluted with water (50 ml), acidified (pH 4) with 1Nhydrochloric acid and extracted with ethyl acetate (2×50 ml). Theorganic phase is washed with saturated sodium chloride (2×40 ml), dried(anhydrous magnesium sulfate) and evaporated to give a solid.Recrystallization from ethyl acetate and hexane affords 1.3 g (55%) ofanalytically pure(2,6-bis(1,1-dimethylethyl)-4-[3-[(methylthio)methyl]-1,2,4-oxadiazol-5-yl]phenol,mp 97°-98° C.

Analyzed for C₁₈ H₂₆ N₂ O₂ S:

Calcd: C, 64.63; H, 7.84; N, 8.38.

Found: C, 64.78; H, 7.87; N, 8.35.

EXAMPLE 742,6-Bis(1,1-dimethylethyl)-4-[3-[(methylsulfonyl)methyl]-1,2,4-oxadiazol-5-yl]phenol

A solution of 1.2 g (0.002 mole) of the hexahydrate magnesium salt ofmonoperoxyphthalic acid in water (2.0 m) is added to 0.4 g (0.001 mole)of2,6-bis(1,1-dimethylethyl)-4-[3-[(methylthio)methyl-1,2,4-oxadiazol-5-yl]phenolin absolute ethanol (4 ml) (exothermic reaction) and the mixture isstirred at room temperature for 18 hours. The clear solution isconcentrated, and the residue dissolved in diethyl ether (50 ml),successively washed with water (30 ml), 10% sodium bicarbonate (30 ml),saturated sodium chloride (2×30 ml), and dried (anhydrous magnesiumsulfate). Evaporation of the ether affords a solid. Recrystallizationfrom diethyl ether gives 0.3 g (71%) of analytically pure2,6-bis(1,1-dimethylethyl)-4-[3-[(methylsulfonyl)methyl]-1,2,4-oxadiazol-5-yl]phenol,mp 153°-155° C.

Analyzed for C₁₈ H₂₆ N₂ O₄ S:

Calcd: C, 58.99; H, 7.15; N, 7.64.

Found: C, 59.16; H, 6.98; N, 7.56.

EXAMPLE 752,6-Bis(1,1-dimethylethyl)-4-(3-trichloromethyl-1,2,4-oxadiazol-5-yl)phenol

Solid3,5-bis(1,1-dimethylethyl)-4-[(2-methoxyethoxy)methoxy]oximebenzamide(6.0 g, 0.02 mole) is slowly added in portions to cold trichloroaceticanhydride (8 ml). Upon completion the mixture is heated at 120° C. for20 minutes, then poured into ice water (20 ml). The oily precipitate isextracted with diethyl ether (2×10 ml) and separated. The organic layeris washed successively with water (2×10 ml), 10% sodium bicarbonate(2×10 ml), and water 2×20 ml), then dried (anhydrous magnesium sulfate).Evaporation of solvent leaves an oil which is purified by flashchromatography (silica gel, ethyl acetate/hexane elution) to give 2.0 g(30%) of analytically pure2,6-Bis(1,1-dimethylethyl)-4-(3-trichloromethyl-1,2,4-oxadiazol-5-yl)phenol, mp 100°-102° C.

Analyzed for C₁₇ H₂₁ Cl₃ N₂ O₂ :

Calcd: C, 52.12; H, 5.40; N, 7.15.

Found: C, 52.21; H, 5.37; N, 6.96.

EXAMPLE 764-(3-Amino-1,2,4-oxadiazol-5-yl)-2,6-bis(1,1-dimethylethyl)phenol

A mixture of 3.8 g (0.014 mole) of N'-cyano-3,5-bis(1,1-dimethylethyl)-4-hydroxybenzenecarboximidamide, 1.0 g (0.014 mole)of hydroxylamine hydrochloride and 4.3 ml (4.2 g, 0.053 mole) ofpyridine in 50 ml of absolute ethanol is stirred at reflux (under anitrogen atmosphere) for 24 hours. The cooled mixture is filtered andevaporated, and the residue is distributed between 250 ml of water and100 ml of ether. The aqueous layer is extracted several times with freshether, and the combined organic layers are washed with brine. Theorganic layer is dried (anhydrous sodium sulfate) and evaporated.Recrystallization of the residue from ethyl acetate/hexane yields 2.0 g(50% yield) of the analytically pure oxadiazol product, mp 167°-170° C.

Analyzed for C₁₆ H₂₃ N₃ O₂ :

Calcd: C, 66.41; H, 8.01; N, 14.52.

Found: C, 66.44; H, 8.12; N, 14.78.

EXAMPLE 77N'-Cyano-3,5-bis(1,1-dimethylethyl)-4-hydroxybenzenecarboximidamide

To a stirred solution of 17.6 g (0.063 mole) of3,5-bis(1,1-dimethylethyl)-4-hydroxybenzenecarboximidic acid, ethylester (E. Muller, A. Rieker, R. Mayer, and K. Scheffler, Ann 645:36(1961)) in 250 ml of methanol (under a nitrogen atmosphere) is added 3.2g (0.076 mole) of cyanamide. The mixture is stirred at reflux for 16hours, cooled, and filtered. The filtrate is evaporated and the residueis digested briefly on the steam bath with 150 ml of 15% ethyl acetatein dichloromethane and refiltered. The final filtrate is condensed to 25ml and chromatographed over silica gel, using 15% ethyl acetate indichloromethane followed by 25% ethyl acetate in dichloromethaneelution. A yield of 11.3 g (65%) of chromatographed amidine product isobtained. Recrystallization of a sample from ethyl acetate/hexane yieldsthe analytically pure product of mp 192°-194°.

Analyzed for C₁₆ H₂₃ N₃ O:

Calcd: C, 70.29; H, 8.48; N, 15.37.

Found: C, 70.22; H, 8.56; N, 15.25.

EXAMPLE 784-[3-(Dimethylamino)-1,2,4-oxadiazol-5-yl]-2,6-bis(1,1-dimethylethyl)phenol

To a stirred mixture of 2.0 g (0.0069 mole) of4-(3-amino-1,2,4-oxadiazol-5-yl)-2,6-bis(1,1-dimethylethyl)phenol and2.0 g (0.0067 mole) of paraformaldehyde in 45 ml of glacial acetic acid(under a nitrogen atmosphere) is added 2.0 g (0.032 mole) of sodiumcyanoborohydride, in portions over ten minutes. The mixture is stirredat room temperature for 24 hours, then cooled in ice and treatedcautiously with 250 ml of ice water. Solid sodium carbonate is addeduntil the reaction mixture becomes slightly basic. The mixture isextracted with ethyl acetate (4×100 ml), and the combined organic layersare washed with brine (2×200 ml), dried (anhydrous sodium sulfate), andevaporated. Recrystallization of the residue from aqueous methanolyields 1.0 g (45% yield) of the analytically pure product, mp 135°-138°.

Analyzed for C₁₈ H₂₇ N₃ O₂ :

Calcd: C, 68.11; H, 8.57; N, 13.24.

Found: C, 67.71; H, 8.31; N, 13.21.

EXAMPLE 795-[3,5-Bis(1,1-dimethylethyl)-4-hydroxyphenyl]-1,3,4-thiadiazole-2(3H)-thione,magnesium (2:1)(Salt)

A 0° C. solution of 9.90 g (24.84 mmol) of5-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-1,3,4-thiadiazole-2(3H)-thionein 100 ml of absolute ethanol is treated with 2.52 g (12.40 mmol) ofMgCl₂.6H₂ O and is stirred for 5 minutes. The reaction is stirred atroom temperature for 4.5 h and concentrated to 50 m. The resultingsolution is poured onto 860 ml of deionized water and fitted to give 6.8g (8.74 g theor., 78%) of the magnesium salt as the dihydrate afterdrying at 80° C. for 18 h.

Calcd: C, 54.65; H, 6.59; N, 7.97; S, 18.89; H₂ O, 5.12.

Found: C, 54.84; H, 6.85; N, 7.99; S, 19.29; H₂ O, 5.82.

Recrystallization of a sample from toluene gives have a melting point of243°-246° C.

EXAMPLE 805-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-1,3,4-thiadiazole-2(3H)-thione,calcium (2:1) (salt)

Calcium chloride dihydrate (1.496, 0.0102 mole) is added in one portionto a solution of5-[3,5-bis(1,1-dimethylethyl)-4-hydroxy-phenyl]-1,3,4-thiadiazole-2(3H)-thione(8.11 g, 0.0204 mole) in tetrahydrofuran (80 m). The resulting mixtureis stirred 2 hours at room temperature before absolute ethanol (80 ml)is added. The mixture is stirred overnight at room temperature. Thesolution is concentrated in vacuo and the residue dissolved intetrahydrofuran and the product is precipitated by the addition ofwater. Filtration and drying at 80° C. in vacuo provides 4.7 g (6.8 gtheor., 68%) 5-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-1,3,4-thiadiazole-2(3H)thione calcium (2:1) (salt), mp212°-231° C., analyzed for 0.31 hydrate.

Calcd: C, 55.37; H, 6.28; N, 8.07.

Found: C, 55.56; H, 6.26; N, 7.95.

EXAMPLE 106 4-Amino-3-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-2,4-dihydro-5H-1,2,4-triazole-5-thione

To a solution of 4.00 g (0.13 mol) of2,6-bis(1,1-dimethylethyl)-4-[5-methythio)-1,3,4-thiadiazol-2-yl-phenolin 100 ml of ethanol is added 20.64 g (0.41 mol) of hydrazine hydrate.The resulting mixture is warmed at reflux for 4 hours then cooled toroom temperature. The reaction is diluted with water and acidified withcold 3N HCl and the precipitate is collected and recrystallized fromN,N-dimethylformamide-water to give 2.10 g (4.17 g theor.; 50%) of4-amino-3-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-2,4-dihydro-5H-1,2,4-triazol-5-thioneas a white solid: mp 260°-270° C.

Calcd: C, 59.97; H, 7.55; N, 17.48.

Found: C, 60.30; H, 7.43; N, 17.40.

EXAMPLE 82 2,6-Bis(1,1-dimethylethyl)-4-[5-methylthio)-1,3,4-oxadiazol-2-yl]phenol

To a 0° C. solution of 17.95 g (0.059 mol) of5-[3,5-Bis(1,1-dimethylethyl)-4-hydroxyphenyl]-1,3,4-oxadiazole-2(3H)-thionein methanol (150 ml) is added 59 mol (0.059 mol) of aqueous 1N NaOH over15 minutes. The reaction is stirred for 15 minutes, then 9.1 g (0.064mol) of iodomethane is added dropwise. The reaction is stirred for 2hours at room temperature, concentrated in vacuo and the resulting solidis recrystallized from methanol-water to give 15.01 g (18.91 g theor.,79%) of2,6-bis(1,1-dimethylethyl)-4-[5-methylthio)-1,3,4-oxadiazol-2-yl]phenol:mp 101°-102° C.

Calcd: C, 63.71; H, 7.55; N, 8.74.

Found: C, 63.75; H, 7.56; N, 8.73.

EXAMPLE 832,6-Bis(1,1-dimethylethyl)-4-[5-methylsulfonyl)-1,3,4-oxadiazol-2-yl]phenol

A mixture of 15.00 % (0.046 mol) of2,6-bis(1,1-dimethylethyl)-4-[5-methylthio)-1,3,4-oxadiazole-2-yl]-phenoland 24.15 g (0.23 mol) of NaHCO₃ in 600 ml of CH₂ Cl₂ is stirred at roomtemperature under N₂ atmosphere for one hour. m-chloroperbenzoic acid(23.74 g of a 80 to 85% pure solid, 0.11 to 0.12 mol) is added to the 0°C. reaction mixture and is stirred for one hour. The reaction is stirredat 25° C. overnight, then treated with 10.00 g (0.12 mol) of NaHCO₃ and9.6 g (0.044°-0.047 mol) of m-chloroperbenzoic acid. The reaction isstirred overnight then washed with aqueous saturated NaHCO₃, water andaqueous saturated NaCl, dried over MgSO₄ and concentrated in vacuo.Recrystallization from ethylacetate-hexane (1:1) gives 7.89 g (16.21 g,theor., 49%) of 2,6-bis(1,1-dimethylethyl)-4-[5-methylsulfonyl)-1,3,4-oxadiazol-2-yl]phenol: mp 162°-163° C.

EXAMPLE 84 N-[5-[3,5-Bis(1,1-dimethylethyl)-4-hydroxyphenyl]-1,3,4-oxadiazole-2-yl]guanidine, monochloride

Sodium (0.68 g, 29.7 mmol) is dissolved in 40 ml of t-butanol under N₂atmosphere. Guanidine hydrochoride (3.31 g, 34.65 mmol) is added to thesodium t-butoxide solution and stirred at room temperature for 0.5 hour.2,6-Bis(1,1-dimethylethyl)-4-[5-(methylsulfonyl)-1,3,4-oxadiazole-2-yl]-phenol(3.50 g, 9.93 mmol) is added and the reaction is warmed at refluxovernight. The cool reaction mixture is concentrated in vacuo and isrecrystallized from methanol-water. The solid is dissolved in diethylether and treated with ethereal HCl and the precipitate is collected andrecrystallized from ethanol-ether to give 1.53 g (3.29 g theor., 46%) ofN-[5-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-1,3,4-oxadiazole-2-yl]guanidine, monochloride as awhite solid: mp 223°-22° C.

Calcd: C, 55.50; H, 7.12; N, 19.03.

Found: C, 54.97; H, 7.22; N, 18.96.

EXAMPLE 85[5-[3,5-Bis(1,1-dimethylethyl)-4-hydroxyphenyl]-1,3,4-oxadiazol-2-yl]cyanamide

To a solution of 3.00 g (8.51 mmol) of2,6-bis(1,1-dimethylethyl)-4-[5-methylsulfonyl)-1,3,4-oxadiazol-2-yl]-phenolin 30 ml of N,N-dimethyl formamide and 5 ml of water is added 3.22 g(76.59 mmol) of cyanamide and 0.9 g (8.51 mmol) of triethylamine. Themixture is warmed at 60° C. overnight with stirring under N₂ atmosphere.The reaction is cooled and partitioned between water and ether. Thelayers are separated and the aqueous layer is acidified with aqueous 6NHCl and the resulting precipitate is isolated by filtration.Recrystallization from acetonitrile-water gives 1.42 g (2.68 g theor.,53%) of the[5-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl-1,3,4-oxadiazol-2-yl]cyanamideas a white solid: mp dec >230° C.

Calcd: C, 64.95; H, 7.05; N, 17.82.

Found: C, 64.60; H, 6.83; N, 17.56.

EXAMPLE 86 N-[5-[3,5-Bis(1,1-dimethylethyl)-4-hydroxyphenyl]-1,3,4-thiadiazol-2-yl]methanesulfonamide

A slurry of 0.52 g (1.7 mmol) of4-(5-amino-1,3,4-thiadiazol-2-yl]-2,6-bis(1,1-dimethylethyl)phenol and0.26 g (2.58 mmol) of triethylamine in 6 ml of toluene is treated with0.30 g (2.58 mmol) of methane sulfonylchloride and warmed at 95°-105° C.for 21 hours under Nitrogen atmosphere. The reaction is cooled to roomtemperature and poured onto cold aqueous 1N NaOH (100 ml) and extractedwith t-butylmethyl ether (3×20 ml). The aqueous layer is acidified withaqueous 1N HCl and filtered to give a yellow solid. Recrystallizationfrom absolute ethanol gives 0.19 g (0.65 g, theor., 29%) ofN-[5-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-1,3,4-thiadiazo-2-yl]methanesulfonamideas a solid: mp 293°-294° C.

Calcd: C, 53.24; H, 6.57; N, 10.96.

Found: C, 53.18; H, 6.65; N, 10.71.

EXAMPLE 87N-[5-[3,5-Bis(1,1-dimethylethyl)-4-hydroxyphenyl]-1,3,4-thiadiazol-2-yl]-acetamide

To a 0° C. suspension of4-(5-amino-1,3,4-thiadiazol-2-yl)-2,6-bis(1,1-dimethylethyl)-phenol (2.4g, 0.0079 mole) in tetrahydrofuran (30 ml) is added triethylamine (1.1ml, 0.0079 mol) followed by acetic anhydride (1.1 g, 0.0108 mole)dropwise. After the addition is complete, the mixture is allowed to warmto room temperature and stir one hour. The solution is concentrated invacuo and the residue resuspended in ether. The product is extracted outwith 1M NaOH (2×) and the combined aqueous layers are acidified with 6MHCl. The resulting precipitate is filtered, washed with water, and driedovernight in vacuo at 80° C. to yield 2.0 g (2.7 g theor., 73%) ofN-[5-3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-1,3,4-thiazol-2-yl]acetamide,mp 326°-328° C.

Calcd: C, 62.22; H, 7.25; N, 12.09.

Found: C, 62.40; H, 7.20; N, 11.76.

EXAMPLE 88(E)-5-[2-[3,5-Bis(1,1-dimethylethyl)-4-hydroxyphenyl]ethenyl]-1,3,4-thiadiazole-2(3H)-thione

Sodium thiomethoxide (0.5 9, 0.007 mole) is added to a solution of(E)-2,6-bis(1,1-dimethylethyl)-4-[2-[5-(methylthio)-1,3,4-thiadiazol-2-yl]ethenyl]-phenol (1.0g, 0.0028 mole) in dimethylformamide (10 ml). The resulting mixture isheated to 75° C. for two hours. The solution is cooled and diluted withwater (20 ml). The mixture is treated with 1M NaOH (6 ml) and theaqueous solution is washed with ether (2×). The aqueous layer is madeacidic by the addition of cold 6M HCl (3 ml) and the product is thenextracted with a 1:1 ethyl acetate/diethyl ether mixture (2×). Thecombined organic layers are washed with brine and dried over MgSO₄.Filtration and concentration in vacuo, followed by recrystallizationfrom ethyl acetate/hexane gives 0.55 g of(E)-5-[2-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]ethenyl]-1,3,4-thiadiazol-2(3H)-thione.(0.98 g theor., 57%), mp 248°-249° C.

Calcd: C, 62.03; H, 6.94; N, 8.04.

Found: C, 61.95; H, 6.87; N, 7.88.

EXAMPLE 89 Ethyl N-[5-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-1,2,4-oxadiazol-3-yl]methanimidoate

A mixture of 0.87 g (0.003 mole) of4-(3-amino-1,2,4-oxadiazol-5-yl)-2,6-bis(1,1-dimethylethyl)phenol and 25ml (22.3 g; 0.15 mole) of anhydrous triethyl orthoformate is stirred atreflux (under a nitrogen atmosphere) for 24 hours. The cooled mixture isevaporated, and the residue is distributed between 75 ml ofdichloromethane and 100 ml of saturated aqueous sodium bicarbonatesolution. The aqueous layer is extracted several times with freshdichloromethane, and the combined organic layers are washed with brine.The organic layer is dried (anhydrous sodium sulfate) and evaporated.Recrystallization of the residue from aqueous acetonitrite yields 0.70 g(67% yield) of ethyl N-[5-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl-1,2,4-oxadiazol-3-yl]methanimidoate, mp 159°-161° C.

Analyzed for C₁₉ H₂₇ N₃ O₃ :

Calcd: C, 66.06; H, 7.88; N, 12.17.

Found: C, 65.90; H, 7.65; N, 12.22.

EXAMPLE 903,5-Bis(1,1-dimethylethyl)-4-[(2-methoxyethoxy)methoxy]benzenecarbothioamide

Into a solution containing 10.0 g (0.03 mole) of3,5-bis(1,1-dimethylethyl)-4-[(2-methoxyethoxy)methoxy]benzonitrile, 5.7ml (0.04 mole) of triethylamine and 14.2 ml (0.18 mole) of pyridine,hydrogen sulfide gas is bubbled over 15 hours. The mixture is pouredinto ice water (110 ml), and an oily precipitate solidifies uponstanding at 0° C. for 15 hours. The solid is thoroughly washed withwater and filtered. Recrystallization from ethyl acetate and hexanegives 7.9 g (71%) of analytically pure 3,5-bis(1,1-dimethylethyl)-4-[2-methoxyethoxy)methoxy]benzenecarbothioamide, mp 113°-115° C.

Analyzed for C₁₉ H₃₁ NO₃ S:

Calcd: C, 64.55; H, 8.84; N, 3.96.

Found: C, 64.60; H, 8.93; N, 3.80.

EXAMPLE 915-[3,5-Bis(1,1-dimethylethyl)-4-hydroxyphenyl]-1,2,4-thiadiazol-3-ol

A solution of 3.15 g (0.009 mole) of3,5-(1-1-dimethylethyl)-4-[(2-methoxyethoxy)methoxyl]benzenecarbothioamidein dry acetone (8 ml) is added in portions to a -20° C. solution of 2.4g (0.018 mole) of oxalyl chloride in acetone (4 ml). After stirring at-20° C. for two hours, the mixture is concentrated to an orange coloredsolid. The crude2-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl)]-4,5-thiazoledione (3.0g) and azidotrimethylsilane (2.5 ml, 0.019 mole) in xylene (25 ml) areheated at 120° C. for 3.5 hours. Evaporation of solvent leaves a solidwhich is recrystallized from ethyl acetate and hexane giving 1.2 g (44%)of analytically pure5-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-1,2,4-thiadiazol-3-ol, mp230°-232° C.

Analyzed for C₁₆ H₂₂ N₂ O₂ S:

Calcd: C, 62.71; H, 7.24; N, 9.14.

Found: C, 62.46; H, 7.35; N, 8.97.

EXAMPLE 92 Ethyl[[[5-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-1,3,4-thiadiazol-2-yl]amino]thioxomethyl]carbamate

To a suspension of4-(5-amino-1,3,4-thiadiazole-2-yl)-2,6-bis(1,1-dimethylethyl)phenol (1.5g, 0.005 mole) in tetrahydrofuran (10 ml) is addedethoxycarbonylisothiocyanate (0.64 g, 0.005 mole) dropwise. Theresulting mixture is stirred 18 hours at room temperature, beforeconcentrating in vacuo. The residue is recrystallized from ethanol/waterto provide 1.7 g (2.2 g theor., 78%) of the title compound after dryingin vacuo at 50° C., mp >250° C.

Calcd: C, 55.02; H, 6.46; N, 12.83.

Found: C, 54.97; H, 6.37; N, 12.59.

EXAMPLE 93N-[5-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-1,3,4-thiadiazol-2-yl]thiourea

A solution of the carbamate (0.8 g, 0.0018 mole), prepared in Example92, in diethyl ether (10 ml) is treated with 4M NaOH (7.3 ml, 0.0293mole). The resulting mixture is heated to reflux for 1.5 hours. Thesolution is cooled and diluted with water (20 ml). The layers areseparated and the aqueous layer is made acidic with 6M HCl (6 ml). Theaqueous layer is extracted with 1:1 EtOAc/Et₂ O (2×) and the combinedorganic layer is washed with saturated NaCl and dried over (MgSO₄).Filtration and concentration in vacuo provides a solid which isrecrystallized from methanol/water to give 0.3 g (0.66 g theor., 44%) ofthe title compound, mp >280° C.

We claim:
 1. A compound of formula (I) ##STR41## a pharmaceuticallyacceptable acid addition or base salt thereof or hydrates; wherein n iszero or one, and W is ##STR42## wherein X is N or S;Z is S or N; withthe proviso that one of Z or X is S and the other is N; Y is (1) C--SR₁wherein R₁ is hydrogen or lower alkyl, (2) ##STR43## wherein R₂ is loweralkyl, (3) ##STR44## wherein R₂ is as defined above, (4) C--NR₁ R₃wherein R₁ is independently as defined above and R₃ is hydrogen or loweralkyl, (5) COR₁ wherein R₁ is independently as defined above, (6) CR₄wherein R₄ is halogen, CF₃, CO₂ R₁, or ##STR45## CH₂ OR₁, Phenyl,##STR46## NR₁ OR₃, S(CH₂)_(m) CO₂ H, CN, H, alkyl, NH(CH₂)_(m) OH, CCl₃,CONR₁ R₃, CSNR₁ R₃, CH₂ X₁₀, CH₂ NR₁₁ R₁₃, NHCSNHCO₂ R₂, CH₂ SR₂, CH₂SO₂ R₂, or NHNH₂, (7) ##STR47## wherein R₁₁ and R₁₃ are hydrogen, loweralkyl or taken together with N form a saturated ring having from 4 to 6carbons; X₁₀ is halogen or NO₂ ; R₅ is H, lower alkyl or OR₁ and R₁, R₂,and R₃ are independently as defined above; and m is 1, 2, or
 3. 2. Acompound of claim 1 wherein n is zero.
 3. A compound of claim 1 whereinn is one.
 4. A compound of claim 2 wherein W is ##STR48## and X, Y, andZ are as defined in claim
 2. 5. A compound of claim 4 wherein Z is N, Xis S and Y is CR₄ wherein R₄ is NHCSNHCO₂ R₂.
 6. A compound of claim 2wherein Y is COR₁, CSR₁, C--NHCN, ##STR49## C--NHCOCH₃, C--NHCOR₅ orC--NHSO₂ R₂.
 7. A compound of claim 3 wherein Y is COR₁, CSR₁, CNR₁ R₂,C--NHCN, ##STR50## C--NHCOCH₃, C--NHCOR₅, or C--NHSO₂ R₂.
 8. A compoundof claim 4 which is 5-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-1,3,4-thiadiazol-2(3H)-one.
 9. Acompound of claim 4 which isN-[5-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-1,3,4-thiadiazole-2-yl]urea.10. A compound of claim 4 which is2,6-bis(1,1-dimethylethyl)-4-[5-(methylthio)-1,3,4-thiadiazol-2-y]-phenol.11. A compound of claim 4 which is[[5-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-1,3,4-thiadiazol-2-y]thio]-aceticacid.
 12. A compound of claim 4 which is2,6-bis(1,1-dimethylethyl)-4-[5-(methysulfinyl)-1,3,4-thiadiazol-2-yl]-phenol.13. A compound of claim 4 which is 2,6-bis(1,1-dimethylethyl)-4-[5-(methylsulfonyl)-1,3,4-thiadiazol-2yl]-phenol.
 14. A compound ofclaim 4 which is2,6-bis(1,1-dimethylethyl)-4-[5-(methylamino)-1,3,4-thiadiazol-2-yl]-phenol.15. A compound of claim 4 which isN-[5-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-1,3,4-thiadiazole-2-yl]-guanidine.16. A compound of claim 4 which isN-[5-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-1,3,4-thiadiazole-2-yl]guanidine,monohydrochloride.
 17. A compound of claim 4 which is5-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-1,3,4-thiadiazol-2-yl]-cyanamide.18. A compound of claim 17 which is the choline salt of the compound ofclaim
 20. 19. A compound of claim 4 which is2,6-bis(1,1-dimethylethyl)-4-[5-[(2-hydroxyethyl)amino]-1,3,4-thiadiazol-2-yl]phenol.20. A compound of claim 4 which is5-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-1,3,4-thiadiazole-2-carbonitrile.21. A compound of claim 4 which is2,6-bis(1,1-dimethylethyl)-4-(1,3,4-thiadiazol-2-yl)phenol.
 22. Acompound of claim 4 which is2,6-(bis(1,1-dimethylethyl)-4-(5-methyl-1,3,4-thiadiazol-2-yl)phenol.23. A compound of claim 4 which is2,6-(bis(1,1-dimethylethyl)-4-[5-(trifluoromethyl)-1,3,4-thiadazol-2-yl]-phenol.24. A compound of claim 4 which is5-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl)]-1,3,4-thiadiazole-2-carboxylicacid, methyl ester.
 25. A compound of claim 4 which is5-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]]-1,3,4-thiadiazole-2-carboxamide.26. A compound of claim 4 which is5-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-1,3,4-thiadiazole-2-carbothioamide.27. A compound of claim 2 wherein W is ##STR51## wherein X, Y and Z areas defined in claim
 2. 28. A compound of claim 27 wherein Y is COR₁,CSR₁, C--NHCN, ##STR52## C--NHCOCH₃, C--NHCOR₅ or C--NHSO₂ W₂.
 29. Acompound of claim 3 wherein W is ##STR53## wherein X, Y and Z are asdefined in claim
 3. 30. A compound of claim 29 which is(E)-2,6-bis(1,1-dimethylethyl)-4-[2-[5-methylthio)-1,3,4-thiadiazol-2-yl]ethenyl]phenol.31. A compound of claim 29 which is(E)-2,6-bis(1,1-dimethylethyl)-4-[2-[5-(methylsulfonyl)-1,3,4-thiadiazol-2-yl]ethenyl]phenol.32. A compound of claim 3 wherein W is ##STR54## wherein X, Y and Z areas defined in claim
 3. 33. A compound of claim 4 which is5-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-1,3,4-thiadiazole-2(3H)-thione.
 34. The choline, sodium, calcium, magnesium, or potassiumsalt of the compound of claim
 33. 35. A compound of claim 4 which is4-(5-amino-1,3,4-thiadiazol-2-yl)-2,6-bis(1,1-dimethylethyl)phenol. 36.A compound of claim 4 which isN-[5-3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-1,3,4-thiadiazol-2-yl]methanesulfonamide.37. A compound of claim 4 which isN-[5-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-1,3,4-thiadiazol-2-yl]-acetamide.38. A compound of claim 29 which is(E)-5-[2-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]ethenyl]-1,3,4-thiadiazole-2(3H)-thione.39. A compound of claim 27 which is5-[3,5-bis(1,1-dimethylethylethyl)4-hydroxyphenyl]-1,2,4-thiadiazol-3-ol.40. A compound of claim 4 which is ethyl[[[5-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-1,3,4-thiadiazol-2-yl]amino]thioxomethyl]carbamate.41. A compound of claim 4 which isN-[5-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-1,3,4-thiadiazol-2-yl]thiourea.42. A compound of claim 1 wherein W is ##STR55## wherein X is S, and Z,and Y are as defined above.
 43. A compound of claim 42 wherein n iszero.
 44. A compound of claim 42 wherein n is one.
 45. A compound ofclaim 43 wherein Z is N and Y is CR₄ wherein R₄ is NHCSNHCO₂ R₂.
 46. Acompound of claim 42 wherein Y is COR₁, CSR₁, C--NHCN, ##STR56##C--NHCOCH₃, C--NHCOR₅, or C--NHSO₂ R₂.
 47. A pharmaceutical compositionfor use as an antiinflammatory agent comprising an antiinflammatoryamount of the compound of claim 42 and a pharmaceutical carrier.
 48. Amethod of treating inflammation in a mammal suffering therefrom whichcomprises administering the compound of claim 42 in unit dosage form.49. A pharmaceutical composition as claimed in claim 42 additionallycomprising an effective amount of a second active ingredient that is anonsteroidal antiinflammatory drug; a peripheral analgesic agent; acyclooxygenase inhibitor; a leukotriene antagonist; an antihistaminicagent; a prostaglandin antagonist or a thromboxane antagonist.
 50. Amethod for treating inflammation in mammals suffering therefromcomprising administering an antiinflammatory effective amount of thecompound of claim 42 in unit dosage form.